versão impressa ISSN 1413-8670
Braz J Infect Dis v.9 n.5 Salvador out. 2005
New therapeutic approaches for HIV and EBV related lymphomas
William J. Harrington, Jr.
Worldwide, more than 40 million individuals are infected with Human Immunodeficiency Virus (HIV). In impoverished countries the number of deaths due to AIDS has rapidly increased, however the infectious and malignant complications of HIV have fallen where potent antiretrovirals (ARV) are widely available. Nonetheless, the prolonged survival of many HIV carriers is likely to result in greater numbers of malignancies among these individuals. Nearly half of all cases of non-Hodgkin's lymphoma (NHL) in AIDS patients are associated with the presence of a gamma herpes virus, Epstein Barr Virus (EBV) or Human Herpes Virus Type 8 (HHV-8).
AIDS NHLs may be categorized into several subtypes. Large cell immunoblastic lymphoma (IBL) and diffuse large cell lymphoma (DLCL) generally occur in the setting of moderate to severe immunosuppression (CD4+ lymphocyte counts below 100 mm3/mL). IBLs and to a lesser degree DLCLs are often associated with EBV and often express the EBV encoded oncoprotein latent membrane protein-1 (LMP-1). LMP-1 may function in a similar manner to tumor necrosis factor receptors by activating cellular proliferation as well as anti-apoptotic functions (Bcl-2). DLCLs are frequently found to contain genetic alterations in Bcl-6. The consequences of these alterations have not been fully defined.
AIDS related Burkitt's lymphoma (BL) generally occurs in relatively immunocompetent patients. AIDS BLs share features with endemic African BL in that both overexpress the oncogene c-myc due to reciprocal translocations that bring the gene under promotor sequences within the Ig loci. Inactivating mutations and deletions of p53 are also common among all types of BL. A distinguishing feature between AIDS BL and endemic BL is that the former is associated with EBV far less frequently than the latter.
A rapidly fatal subtype of AIDS NHL is Primary Central Nervous System Lymphoma (PCNSL). These tumors occur in the most immunosuppressed patients and are virtually always associated with EBV. Detection of EBV sequences in the CSF by polymerase chain reaction (PCR) coupled with positive Thallium spectroscopy has proven to be an accurate diagnostic tool. Standard therapy with conventional chemotherapy combined with radiation therapy results in only about a 2-month survival.
A peculiar subtype of AIDS NHL is primary effusion lymphoma (PEL). This tumor is one of three proven to be associated with HHV-8; the other two are Kaposi's sarcoma and multicentric Castleman's diseases. PEL usually presents as a malignant pleural, pericardial, or peritoneal effusion and is often initially misdiagnosed as an infectious process. Usually PEL cells contain multiple copies of HHV-8 (60 to 80) as well as EBV. These tumors tend to be rapidly fatal although recent data from our laboratory suggests that some PEL lines are quite sensitive to antiviral agents.
Therapy of AIDS NHL remains disappointing. Polychemotherapy regimens have produced similar results although regimens that combine potent antiretrovirals with conventional chemotherapy may prove superior. In general, our experience has been that patients concomitantly diagnosed with HIV infection and lymphomas do better with antiretroviral and antilymphoma therapy than do those who develop lymphoma after becoming refractory to antiretrovirals. Probably the best reported results for chemotherapy in AIDS NHL were from Dr. Little's group at the National Cancer Institute. Using the EPOCH regimen, the group achieved remission in 22 of 24 patients with a progression free survival of 23 months. These patients had favorable prognostic factors (median CD4+ lymphocyte count of 233 mm3/mL). It is important to comment on the potential enhanced toxicity of adding rituximab to CHOP chemotherapy that has recently been reported in a large multi-center trial conducted by the AIDS Malignancy Consortium. In this study (AMC 010), the addition of rituximab to standard-dose CHOP led to increased infectious complications and deaths attributable to sepsis. It is possible that delayed recovery of humoral immunity could contribute to this increased risk of life-threatening bacterial infections in HIV-infected patients (manuscript submitted).