The etiology of Kaposi's sarcoma (KS) is complex and multifactorial.^[1] Underlying immunosuppression clearly increases the risk of KS; thus, the incidence of KS in organ transplant recipients receiving immunosuppressive therapy is 400-500 times higher than that in the general population. Genetic factors related to various immune functions may also play a role.^[2,3]

Aside from immunosuppression, infection by human herpesvirus type 8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus [KSHV]) is required for the development of KS in humans.^[4] Genomic material from HHV-8 is found within tissues from virtually all types of KS, including AIDS-KS, classic Mediterranean KS, endemic KS from Africa, and transplantation-associated KS. A number of HHV-8-encoded gene products have been identified which have the capability to induce the multiple aberrations found microscopically within KS tissues and macroscopically within affected patients.

Transmission of HHV-8

Several studies of men who have sex with men (MSM) have shown that HHV-8 may be transmitted sexually.^[5] Thus, increasing numbers of sexual partners, history of a sexually transmitted disease, and presence of underlying HIV infection are all risk factors for HHV-8 infection among MSM.^[6,7] Deep kissing, sex with a partner with KS, and use of inhaled nitrites or amyl nitrite capsules are also risk factors for HHV-8 infection among HIV-negative MSM without KS.^[8] Increasing numbers of heterosexual partners is a risk factor for HHV-8 infection among heterosexual persons studied in Africa.^[9]

Recent data have also identified infected saliva as a potential source of HHV-8 transmission.^[8,10] Investigators at the University of Washington, Seattle, looked for the presence of HHV-8 in various anatomic sites and secretions from a group of 50 HHV-8-infected men without KS.^[8] Of interest, saliva was the secretion that was the most consistently infected over time, with HHV-8 detected in 34% of oropharyngeal samples, 0.3% of urethral swabs, 1% of anal swabs, and 5% of semen samples. Furthermore, the titers of HHV-8 in mucosal pharyngeal swabs and saliva were 2-3 logs higher than those found in semen, prostatic secretions, or anal-rectal swabs.

The discovery that HHV-8 may be transmitted by infected saliva may explain the increased risk of KS among MSM who engage in deep kissing^[8] or oroanal sexual contact,^[11] and may also explain the widespread epidemic of KS among children in Africa. In this regard, Sitas and colleagues^[12] have shown a relationship between maternal HHV-8 infection and HHV-8 infection among their children, with no statistically significant relationship to the father's HHV-8 status. These children appear to acquire HHV-8 infection at some stage after birth, with increasing rates of infection over time. Sexual or parenteral routes of HHV-8 transmission would be most unlikely in these children. Salivary transmission is possible, however. In resource-rich areas of the world, the weaning of children from milk to solid foods is accomplished with the use of commercially available blended baby foods. Such products are not available in resource-poor regions, where mothers commonly premasticate the food for their infants, depositing this food, admixed with maternal saliva, into the baby's mouth. It is possible that the epidemic of KS in African children may have evolved from this practice.

New Data on HHV-8 Transmission

In an attempt to study the transmission of HHV-8 from mothers to their children, Phiri and colleagues^[13] studied 3136 mother-infant pairs from Zambia, Africa. The overall seroprevalence of HHV-8 in the mothers at time of delivery was 40% (1259 of 3136), and 30% were HIV-1-seropositive. HIV-1-infected mothers were more likely to be infected with HHV-8 than were HIV-1-seronegative women. A cohort of 494 mother-infant pairs was studied again 12 months after delivery. The HIV-1 seroconversion rate in the mothers was 3% during the year, and the HHV-8 seroconversion rate was 10% during the same period. Among the infants, 20% developed new HHV-8 infections and 8% seroconverted to HIV-1. HHV-8 transmission was more likely in infants whose mothers were coinfected with both HIV-1 and HHV-8. All infants in the study had been breast-fed, although information was not available regarding presence of HHV-8 within breast milk per se. It is of interest that the infants were more likely to develop HHV-8 infection (20%) than HIV-1 infection (8%) during their first 12 months of life. Furthermore, HHV-8 infection appears quite prevalent among Zambian women and their children.

Webster-Cyriaque and colleagues^[14] from the University of North Carolina at Chapel Hill studied the presence of the HHV-8 genome within throat washings, peripheral blood, and buccal scrapings from a group of immunocompetent, HIV-negative, HHV-8-seropositive patients in the United States, who did not have clinical evidence of KS. Presence of HHV-8 latency-associated nuclear antigen (LANA) was detected in the majority of buccal epithelial cell specimens of these individuals, indicating that the saliva may be a potential source of HHV-8 transmission within the general population of immunocompetent individuals.

The prevalence of HHV-8 infection among 192 healthy blood donors in the United Kingdom was studied by Kumar and colleagues.^[15] This study differed from previous studies in that both serologic methods and direct PCR of peripheral blood mononuclear cells were employed. A nested PCR method was used to amplify a 172-base-pair fragment of ORF 26 and a 246-base-pair fragment of the VR1 region of K1. A total of 16% (31 of 192 individuals) tested positive for the presence of the HHV-8 genome, with subsequent confirmation by sequencing. A total of 34% were seropositive for HHV-8, while 42% were seropositive for cytomegalovirus, 87% for Epstein-Barr virus, 21% for herpes simplex virus (HSV) type 1, and 1% for HSV-2. This study again demonstrates the fact that healthy, immunocompetent individuals may be infected by HHV-8, without clinical illness.

Epidemiology of KS in the Era of HAART

One of the most fascinating outcomes of the widespread use of highly active antiretroviral therapy (HAART) in the United States and Europe has been the remarkable decline in Kaposi's sarcoma. Thus, in the Multicenter AIDS Cohort Study (MACS) of MSM, rates of KS fell by 66% when comparing the periods 1989-1994 and 1996-1997, coincident with the period in which HAART use increased substantially.^[16] In the Swiss HIV Cohort Study, Ledergerber and colleagues^[17] demonstrated a substantial reduction in incident cases of KS, with a relative risk of 0.08 when comparing data from 1992-1994 with data from July 1997 to June 1998, after the introduction of HAART. Similar data were reported from a large international collaborative study that evaluated cancer incidence data from 23 prospective studies, including 47,936 HIV-infected individuals from North America, Europe, and Australia.^[18] In this study, the adjusted incidence rate for KS declined from 15.2 per 1000 person-years in 1992-1996 to 4.9 per 1000 person-years in 1997-1999, representing a rate ratio of 0.32.

The remarkable decline in the incidence of KS in the era of HAART could be explained by the ability of potent antiretroviral therapy to inhibit HIV replication and ameliorate HIV-induced immunosuppression. An alternative possibility, however, is that HHV-8 prevalence and transmission rates may have fallen within the same time interval. To address this issue, Osmond and colleagues^[19] recently studied the prevalence of HHV-8 infection among MSM in San Francisco, California, over time, using blood samples acquired in 1978-1979, 1984-1985, and 1995-1996. Of interest, the prevalence of HHV-8 infection was 26.5% in 1978-1979 and remained essentially unchanged over time. In contrast, the prevalence of HIV infection declined from 49.5% in 1984-1985 to 17.6% in 1992-1993. With regard to sexual behaviors, the rates of unprotected oral intercourse remained relatively constant over time (60% to 90%) but the proportion of men practicing unprotected receptive anal intercourse decreased from 54% in 1984 to 11% in 1993. These data would suggest that the decline in KS documented in the HAART era is not due to any significant decrease in the prevalence of HHV-8, or to any change in the sexual behaviors (oral-anal contact) that are thought to be operative in terms of HHV-8 transmission. Instead, the recent decline in KS is likely to a consequence of the improved immune function and decrease in HIV-1 viral load induced by HAART.

Use of HAART to Treat KS

In light of the significant decline in KS incidence coinciding with the widespread use of HAART,^[17,18] and the known importance of the HIV tat gene and its protein product in the pathogenesis of AIDS-related KS, the efficacy of HAART as a specific treatment for KS has been entertained. At this time, no prospective trials addressing this issue have been completed. However, there are several anecdotal reports of KS regression in patients receiving HAART alone.^[20-22]

A recent study of 78 patients with AIDS-related KS, who had previously received therapy for KS, sought to determine the time to treatment failure both before and after the initiation of HAART therapy.^[23] The median time to KS treatment failure before starting HAART was 6 months. In contrast, the median time to KS treatment failure from the start of HAART was 1.7 years (P < .001). Of interest, loss of HIV viral control (defined as HIV-1 RNA levels > 5000 copies/mL) was associated with a statistically increased risk of requiring therapy for KS, but change in CD4+ cell count was not.

Several new studies of the impact of HAART on KS were presented at the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies. To illuminate the ability of specific types of antiretroviral agent to treat known KS, Bower and colleagues^[24] reported their experience with a cohort of 8640 HIV-infected patients cared for at the Chelsea and Westminster Hospital in London, United Kingdom. Of these patients, 1204 were diagnosed with KS, including 198 cases diagnosed after 1996 when HAART became widely available. The incidence of KS within the cohort was as high as 30 cases per 1000 person-years of follow-up from the 1980s through 1995, then fell to 7.6 cases per 1000 person-years during 1995-1996, when dual antiretroviral therapy was commonly administered. Most recently, the incidence fell to 0.03 cases per 1000 person-years between 1997 and 2001, when HAART was routinely administered. With regard to the characteristics of the underlying HIV-1 disease, no differences between the pre-HAART and post-HAART era were observed in terms of nadir CD4+ cell counts or CD4+ cell count at the time of KS diagnosis; however, patients with KS diagnosed in later time periods were statistically more likely to have KS as their first AIDS-defining diagnosis. Univariate and multivariate analyses were performed to determine the factors associated with the diagnosis of KS since 1996. Factors included in the model were age, gender, ethnic origin, nadir CD4+ cell count, most recent CD8+ cell count (as a surrogate for presence of cytotoxic T lymphocytes), and antiretroviral drug exposure. In the multivariate analysis, the factors that were statistically associated with an increased risk of Ks were age (2% increased risk of KS per year older at entry into the cohort), a nadir CD4+ cell count < 150 cells/mm³, and lack of antiretroviral drug exposure. Of interest, the rate ratios for KS were statistically decreased for all types of antiretroviral drug use, as shown in Table 1.

Table 1. Rate Ratios for Development of KS, Based Upon Antiretroviral Drug Exposure

*statistically significant on multivariate analysis, compared with no therapy. NRTI(s) indicates nucleoside reverse transcriptase inhibitor(s); PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor

During the HAART era, a total of 198 patients were diagnosed with KS. Of these, 82% had never received HAART, primarily because KS was their first HIV/AIDS-related illness. Only 35 patients (18%) were taking HAART at the time KS was diagnosed, and it is noteworthy that HAART was failing in 30 of these 35, as shown in Table 2.

Table 2. Patients Who Developed KS While Receiving HAART

This study is of importance in defining the factors associated with KS in the era of HAART. It is clear that the majority of these patients have simply not been receiving HAART, and among those who are treated, development of KS is associated with virologic and immunologic treatment failure. This study thus emphasizes, once again, the importance of effective antiretroviral therapy in preventing the development of KS. Moreover, apparently any effective antiretroviral regimen will likely be efficacious in preventing KS.

Update: Therapy of AIDS-Related KS

Phase 3 Study of IM 862

Several papers were presented regarding treatment options for patients with AIDS-related KS (AIDS-KS). Ariela Noy^[25] presented data from the National Cancer Institute (NCI)-sponsored AIDS Malignancy Consortium regarding IM 862, a compound initially isolated from extracts of the thymus glands of cows in Russia and used as an immune adjuvant in that country. Initial work by Gill and colleagues indicated that this dipeptide had antiangiogenic properties, and a subsequent randomized phase 2 trial^[26] in 44 patients with advanced AIDS-KS documented a response rate of 36%, following administration of a fixed dose of 5 mg given intranasally either every other day or in 5-days-on, 5-days-off cycles. In an attempt to ascertain the potential value of IM 862 in patients with AIDS-KS, Noy and colleagues^[25] initiated a phase 3 study of IM 862 (5 mg intranasally every other day) vs placebo. A total of 202 patients were enrolled between December 1998 and February 2001. Eligibility criteria included biopsy-proven KS with 5 or more measurable lesions on skin or mucus membranes in patients who were not believed to require systemic chemotherapy. Antiretroviral therapy was required to be unchanged for at least 8 weeks before enrollment, to exclude the possibility that any effect might have been due to effective HAART. The baseline characteristics and results are summarized in Table 3.

Table 3. Phase 3 Study of IM 862 for AIDS-KS

These results were disappointing, with no differences seen between placebo recipients (ie, patients on HAART alone) and those receiving HAART plus IM 862. The failure of IM 862 may be related to inadequate dosing, as further preclinical work indicated the need for a much higher dose, or to the fact that IM 862 may simply be ineffective. It is possible that the efficacy of IM 862 in earlier trials^[26] was actually the result of HAART, not IM 862. Unfortunately, further evaluation of this compound is unlikely because the company has stopped all future development.

Liposomal Anthracycline Combined With Antiangiogenic Therapy

Liposomal encapsulation alters drug kinetics, resulting in a prolonged half-life. Furthermore, increased accumulation in KS tissues -- as high as 5- to 50-fold compared with the normal surrounding tissue -- results in enhanced cellular toxicity. Liposome-encapsulated daunorubicin and doxorubicin have been studied extensively in the treatment of AIDS-KS.^[27,28] The dose-limiting toxicity of liposomal daunorubicin is bone marrow suppression, while liposomal doxorubicin is associated with hand/foot syndrome, consisting of pain and palmar-plantar erythema. Compared with combination chemotherapy with doxorubicin, bleomycin, and vinblastine (ABV) or bleomycin and vinblastine (BV), the toxicity of liposomal anthracyclines is substantially reduced. Hair loss, in particular, is rare with the liposomal preparations. In addition, the incidence of cardiac toxicity appears to be reduced, even after high cumulative doses. In 2 independent phase 3 studies, both liposomal daunorubicin (40 mg/m² administered intravenously [IV] every 2 weeks) and doxorubicin (20 mg/m² IV every 2 weeks) as single agents had activity equivalent or superior to combinations of ABV or BV.^[27,28] Moreover, the duration of response, time to treatment failure, and overall survival were also improved compared with those achieved with the combination chemotherapy regimens.^[27,28]

Interleukin-12 (IL-12) has known antiangiogenic properties through induction of interferon-gamma with subsequent production of inducible protein 10 (IP-10). This cytokine is also known to have immunostimulatory properties in respect of natural killer cells. Because preclinical models have indicated potential synergy between antiangiogenic and cytotoxic therapies, Little and colleagues^[29] at the NCI initiated a phase 2 clinical trial of liposomal doxorubicin (20 mg/m² IV every 3 weeks) plus IL-12 (300 ng/kg subcutaneously twice weekly) for 18 weeks. The active treatment phase was then followed by maintenance IL-12 (500 ng/kg twice weekly). A total of 23 patients with advanced KS and HIV-1 disease have been accrued to date. At baseline, the median CD4+ cell count was 142 cells/mm³ (range, 14-760), and the median HIV-1 RNA level was 2.10 log₁₀ copies/mL. The median Karnofsky performance status was 80%, and all patients had extensive tumor involvement (n = 20), a CD4+ cell count < 150 cells/mm³, or both, leading to very poor T-I-S scores (T = clinical extent/placement of tumor; I = immune status/CD4+ cell count; S = assessment of HIV-related systemic illness).

At the time of reporting, 20 patients were evaluable, of whom 17 (85%) had experienced a partial response. The median time to response was relatively short, at 2 cycles. Of patients with CD4+ cell counts < 150 cells/mm³, 2 progressed during the chemotherapy phase and 3 progressed during maintenance IL-12. In patients with CD4+ cell counts > 150 cells/mm³, 3 patients progressed during maintenance IL-12. Toxicity included grade 4 neutropenia and grade 4 elevations of aspartate aminotransferase. Two patients developed nonneutropenic sepsis, believed to be unrelated to study treatment. The median progression-free survival was 6.8 months at the time of analysis, shorter than initially postulated from results in earlier trials of IL-12 alone. The reasons for the short progression-free survival are unknown, but may be related to the fact that these patients had far-advanced disease with regard to both KS and HIV-1. Thus, they may have required a longer period of cytotoxic chemotherapy before switching to maintenance IL-12 alone. An amendment to this protocol was recently initiated, in which patients with residual KS after 18 weeks of liposomal doxorubicin plus IL-12 may then receive paclitaxel every 3 weeks plus continued IL-12 until near or complete remission. At that time, cytotoxic chemotherapy will be discontinued and IL-12 alone will be given during maintenance.

References

1. Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med. 2000;342:1027-1038.
2. Lehrnbecher T, Foster CB, Zhu S. Variant genotypes of Fc gamma RIIIA influence the development of Kaposi's sarcoma in HIV infected men. Blood. 2000;95:2386-2390.
3. Nagy K, Kemeny B, Horvath A. HIV co-receptor mutation affects course of Kaposi's sarcoma in HIV/HHV8 positive patients. Program and abstracts of the 1st IAS Conference on HIV Pathogenesis and Treatment; July 8-11, 2002; Buenos Aires, Argentina. Abstract 274.
4. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266:1865-1869.
5. Gao S-J, Kingsley L, Hoover DR, et al. Seroconversion to antibodies against Kaposi's sarcoma associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med. 1996;335:233-241.
6. Martin J, Ganem DE, Osmond DH, et al. Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med. 1998;338:948-954.
7. Grulich AE, Olsen SJ, Luo K, et al. Kaposi's sarcoma-associated herpesvirus: A sexually transmissible infection? J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:387-393.
8. Pauk J, Huang-M-L, Brodie SJ, et al. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med. 2000;343:1369-1377.
9. Sitas F, Carrara H, Beral V, et al. Antibodies against human herpesvirus 8 in black South African patients with cancer. N Engl J Med. 1999;340:1863-1871.
10. Brodie SJ, Johnson A, Vieira J, Coelle D, Wald A, Corey L. Oral shedding and propagation of HHV8 in pharyngeal lymphoid tissues: Potential cofactor role of HIV. Program and abstracts of the 5th International AIDS Malignancy Conference; April 23-25, 2001; Bethesda, Maryland. Abstract 48.
11. Grulich AE, Kaldor JM, Hendry O, et al. Risk of Kaposi's sarcoma and oro-anal sexual contact. Am J Epidemiol. 1997;145:673-679.
12. Sitas F, Newton R, Boshoff C. Increasing probability of mother-to-child transmission of HHV8 with increasing maternal antibody titer for HHV8. N Engl J Med. 1999;340:1923.
13. Phiri S, Brayfield B, Muyanga J, et al. Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8) and HIV-1 infections in a cohort of mother/infant pairs in Zambia. Program and abstracts of the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies; April 22-24, 2002; Bethesda, Maryland. Abstract 18.
14. Webster-Cyriaque J, Quinlivin EB, Kendrick K. Detection of KSHV in the saliva of immunocompetent and immunosuppressed individuals. Program and abstracts of the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies; April 22-24, 2002; Bethesda, Maryland. Abstract 25.
15. Kumar N, Porter SR, Teo CG. Prevalence of HHV-8 in healthy blood donors. Program and abstracts of the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies; April 22-24, 2002; Bethesda, Maryland. Abstract 39.
16. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:853-860.
17. Ledergerber B, Telenti A, Effer M. Risk of HIV related Kaposi's sarcoma and non-Hodgkin's lymphoma with potent anti-retroviral therapy: Prospective cohort study. BMJ. 1999;319:23-24.
18. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus infected adults. J Natl Cancer Inst. 2000;92:1823-1830.
19. Osmond DH, Buchbinder S, Cheng A, et al. Prevalence of Kaposi's sarcoma associated herpesvirus infection in homosexual men at beginning of and during the HIV epidemic. JAMA. 2002;287:221-225.
20. Tavio M, Nasti G, Spina M, Errante D, Vaccher E, Tirelli U. Highly active antiretroviral therapy in HIV related Kaposi's sarcoma. Ann Oncol. 1998;9:923.
21. Lebbe C, Blum L, Pellet C, et al. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV related Kaposi's sarcoma. AIDS. 1998;12:F45-F49.
22. Conant MA, Opp KM, Poretz D et al. Reduction of Kaposi's sarcoma lesions following treatment of AIDS with ritonavir. AIDS. 1997;11:1300-1301.
23. Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B. Highly active antiretroviral therapy prolongs time to treatment failure in Kaposi's sarcoma. AIDS. 1999;13:2105-2111.
24. Bower M, Portsmouth SD, Mandalia S, Nelson M, Gazzard BG. HIV-1 related Kaposi's sarcoma n the highly active antiretroviral therapy (HAART) era. Nonnucleoside reverse transcriptase inhibitors are as effective at preventing KS as protease inhibitors. Program and abstracts of the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies; April 22-24, 2002; Bethesda, Maryland. Abstract 4.
25. Noy A, Gill P, Scadden D, et al. Angiogenesis inhibitor IM 862 is ineffective against AIDS-KS in a randomized, placebo controlled trial. Program and abstracts of the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies; April 22-24, 2002; Bethesda, Maryland. Abstract 5.
26. Tulpule A, Scadden DT, Espina BM, et al. Results of a randomized study of IM862 nasal solution in the treatment of AIDS related Kaposi's sarcoma. J Clin Oncol. 2000;8:716-723.
27. Gill PS, Wernz J, Scadden DT, et al. Randomized phase III trial of liposomal daunorubicin (DaunoXome) versus doxorubicin, bleomycin, vincristine (ABV) in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996;14:2353-2364.
28. Northfelt DW, Dezube B, Thommes JA, et al. Pegylated liposomal doxorubicin versus doxorubicin, bleomycin and vincristine in the treatment of AIDS related Kaposi's sarcoma: Results of a randomized phase III clinical trial. J Clin Oncol. 1998;16:2445-2451.
29. Little RF, Aleman K, Pluda JM, et al. Preliminary results of combination liposomal doxorubicin and interleukin-12 (IL12) followed by chronic IL-12 maintenance therapy in advanced AIDS related Kaposi's sarcoma. Program and abstracts of the 6th International Conference on Malignancies in AIDS & Other Immunodeficiencies; April 22-24, 2002; Bethesda, Maryland. Abstract 6.