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AIDS Malignancies in the Era of Highly Active Antiretroviral Therapy

AIDS Malignancies in the Era of Highly Active Antiretroviral Therapy

ABSTRACT: The introduction of highly active antiretroviral therapy (HAART) has had a dramatic impact on the morbidity and mortality of individuals living with human immunodeficiency virus (HIV). In addition to contributing to declines in the incidence of several opportunistic infections, HAART is affecting the incidences of several acquired immunodeficiency syndrome (AIDS)-defining malignancies. The incidence of Kaposi’s sarcoma (KS) and primary central nervous system lymphoma (PCNSL) has dropped precipitously since the introduction of HAART in 1995. Systemic non-Hodgkin’s lymphoma (NHL) appears to be declining in incidence as well, but to a lesser degree than KS and PCNSL. On the contrary, the incidence of invasive cervical carcinoma has not significantly changed in the HAART era. The impact of HAART on the epidemiology of other HIV-associated malignancies, including Hodgkin’s disease and anal carcinoma, remains unclear. Data regarding the impact of HAART on the natural history and treatment outcomes of HIV-associated malignancies are limited. The possibility of direct and indirect roles of HIV in HIV-related carcinogenesis suggests that antiretroviral therapy may be an important component of the treatment strategy for several HIV-related malignancies. Patients with HIV-NHL treated with HAART in addition to chemotherapy experience fewer intercurrent opportunistic infections. Furthermore, the simultaneous administration of HAART and chemotherapy does not appear to significantly increase toxicity. Whether the combination of HAART and standard therapy results in improved survival remains uncertain. This two-part article, which will conclude in the May 2002 issue, analyzes the impact of HAART on the incidence, clinical course, and outcomes of each of the AIDS-related malignancies. [ONCOLOGY 16:441-459, 2002]

The interplay of the immune system and
cancer was recognized prior to the acquired immunodeficiency syndrome (AIDS)
epidemic. In the setting of immunosuppression (either congenital or acquired),
there is an increased risk of several malignancies, including non-Hodgkin’s
lymphoma (NHL), Kaposi’s sarcoma (KS), nonmelanoma skin cancers, and
anogenital neoplasia (see Table 1).[1-10] The relationship between
immunosuppression and malignancy is not entirely understood. Putative mechanisms
of tumorigenesis in immunosuppressed patients implicate impaired immune
surveillance and uncontrolled viral replication in a permissive environment. The
clinical course of immunodeficiency-related malignancies is variable. In some
cases of transplantation-related malignancy, reducing the level of
immunosuppression results in restoration of antigen-specific cytotoxic
lymphocyte responses with subsequent regression of the tumors.

Though AIDS-related malignancies share some features with
malignancies arising in the setting of congenital or iatrogenic immune
deficiencies, they are distinct in several ways. The AIDS-defining malignancies
include KS, systemic NHL, central nervous system NHL (CNS-NHL), and cervical
cancer. As is the case with congenital or iatrogenic immunodeficiency-related
malignancies, the pathogenesis of AIDS-related malignancies remains unclear.
AIDS-related neoplasms are associated, to varying degrees, with specific
viruses, such as Epstein-Barr virus, human herpesvirus 8 (HHV-8), and human
papillomavirus (see Table 2, Table
3
, and Table 4).[1,5,11-16] Unique to AIDS-related
malignancies is the direct role that HIV may play in tumorigenesis.

Malignancies that arise in the setting of HIV infection follow
an aggressive clinical course. Historically, therapies effective against these
malignancies were difficult to use in individuals with already-impaired immune
function and poor bone marrow reserve. Until recently, the possibility of
restoring the immune system of HIV-infected individuals proved elusive. The
phenomenon of immune reconstitution has been observed in many individuals
treated with highly active antiretroviral therapy (HAART). Whether such patients
truly recover normal immune function is questionable. In fact, qualitative
studies of immune function suggest that the T-cell repertoire may not be
completely restored once significant damage has occurred. Similarly, there are
limited data regarding the function of antigen-presenting cells and natural
killer cells following HAART. As such, the impact of HAART on the incidence,
clinical course, and outcomes of each of the AIDS-related malignancies is
variable. This two-part article, which will conclude in next month’s issue,
will attempt to describe the changes in the epidemiology, treatment, and
outcomes of individuals with HIV and cancer in the HAART era.

Kaposi’s Sarcoma

Epidemiology and Pathogenesis

The epidemic form of KS was first observed in the late 1970s in
homosexual men, heralding the AIDS epidemic.[1,17] Between 1981 and 1983, KS was
the initial AIDS diagnosis in 50% of non-injectional drug-using homosexual
men in New York.[18] Kaposi’s sarcoma remains the most common AIDS-associated
malignancy.[11] From the early 1980s through the 1990s, the lifetime risk of
developing KS for an HIV-infected homosexual male was approximately 40% to
50%.[7] HIV-infected homosexual men have the highest risk of developing KS. The
relative risk (RR) of developing KS in HIV-infected men with a history of sex
with men is 106,000, compared to a relative risk of 13,000 in men who deny a
history of sex with men.[5] The relative risk in HIV-infected women is unknown,
but the rare cases of KS in women are usually in those who have had a bisexual
male partner.[1,19]

The impact of HAART on the epidemiology and clinical course of
KS is best understood in the context of the pathogenesis of KS. An interaction
between HHV-8, immunosuppression, and HIV appears to be necessary for the
development of AIDS-associated KS. The observed epidemiology of KS suggested a
sexually transmissable etiology. Since its identification in 1994, HHV-8 has
been found in nearly all KS tissue specimens of both HIV-infected and
HIV-uninfected individuals.[1,20] Its sexual transmission is strongly suggested
by its association with number of homosexual partners.[21] Aside from this
sexual risk factor, no specific sexual practices are associated with HHV-8
infection. While HHV-8 DNA has been detected in saliva, mucous membranes, semen,
and gastrointestinal mucosa from HIV-infected individuals and from organ
allografts, its exact mode of transmission is unclear.[18,22-24] Recently,
saliva has been identified as a likely mode of transmission, with the oropharynx
as a portal of entry.[25]

HHV-8, a gamma-2 DNA herpesvirus, shares some homology with
Epstein-Barr virus and herpesvirus saimiri.[18] It is lymphotrophic and has been
documented in the lymph nodes and peripheral B cells of seropositive
individuals.[1,18] A potential etiologic role of HHV-8 in the pathogenesis of KS
is inferred from epidemiologic observations. The seroprevalence rates of HHV-8
correlate with incidence rates for KS in various subpopulations (see Table
5
).[1,5,18,26,27] Furthermore, infection with HHV-8 precedes and predicts
development of KS.[21] The Multicenter AIDS Cohort Study (MACS) reported of 40
men with a history of sex with men who developed KS, 80% were seropositive for
HHV-8 prior to the development of KS, compared to 18% of men with a history of
sex with men who were HIV-positive but did not develop KS within the study
period.[7]

The latent form of HHV-8 predominates in KS.[18] Interestingly,
HHV-8 encodes many latent and lytic genes that are homologs of human cellular
genes involved in inflammation, cell cycle regulation, and angiogenesis.[18] An
example is the viral homolog of cellular D-type cyclin that can activate
kinases, resulting in phosphorylation and inactivation of the retinoblastoma
tumor suppressor gene. A viral homolog of the human bcl-2 gene product inhibits
apoptosis. Expression of vbcl-2 has been shown to increase with advancing stages
of KS.[18,28,29] HHV-8 also encodes a G protein-coupled receptor (vGPCR) that
is homologous to the human interleukin (IL)-8 receptors CXCR1 and CXCR2.[18]
This vGPCR is capable of inducing angiogenesis in vitro. Viral homologs of IL-6,
basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF)
may be important autocrine and paracrine growth factors for KS tumor cells.

HIV may act both directly and indirectly as a cofactor in the
development of KS. The HIV-1-encoded tat protein has been shown to cause
interferon (IFN)-gamma-primed endothelial cells to proliferate and form
tubelike structures that can secrete angiogenic and growth factors.[30]
Innoculation of the tat gene and bFGF into nude mice results in the development
of tumors similar to KS.[30-32]

A potential unifying pathogenic model explaining the interplay
of HIV infection and HHV-8 postulates that individuals at risk for KS have
activated endothelial and inflammatory cells caused by chronic antigenic
stimulation (ie, HIV infection).[33] These cells are then infected by Kaposi’s
sarcoma herpesvirus (known as KSHV or HHV-8) via circulating mononuclear cells
harboring HHV-8. A milieu of inflammatory proteins allows for the development of
spindle cells, which, in turn, secrete growth factors (FGF and VEGF) leading to
angiogenesis, edema, and KS lesions. The expression of KSHV gene products
further stimulates angiogenesis and growth, resulting in the development of a
clonal tumor.[18,30,34]

Some degree of immune deficiency appears to be necessary for KS
development. Individuals infected with HHV-8 with intact immune systems are at
very low risk for developing KS. In parts of Italy with seroprevalence rates of
20%, the annual risk of classic KS is less than 0.1%.[1] Up to 20% to 30% of
transplantation-related KS cases show spontaneous regression with
discontinuation of immunosuppressive therapies.[7] Although KS can occur at any
CD4 count, the risk of KS increases as the CD4 count falls and more advanced
disease is common with lower CD4 counts.[5]

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