Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy

Primary effusion lymphoma (PEL) is a rare HIV-associated high-grade B cell lymphoma. A poor outcome and co-infection with herpesvirus-8 (HHV-8) and Epstein–Barr Virus (EBV) are the main characteristics of PEL. We report one observation of a patient with AIDS-related PEL who achieved complete remission with a combination of cidofovir, IFN-α and highly active antiretroviral therapy (HAART), without cytostatic chemotherapy. A 42-year-old homosexual, drug addict, HIV and hepatitis C virus co-infected white man had been treated with stavudine, lamivudine and indinavir since October 1997. He presented in March 1998 with a 2 month course of fever and nocturnal sweats. On admission, clinical examination revealed ascitis and right pleural effusion. There was no cutaneous Kaposi's sarcoma. His CD4 cell count was 98 cells/μl. A total body scan confirmed ascitis and unilateral pleural effusion but did not disclose a tumoral mass. A liver biopsy demonstrated hepatitis C-related cirrhosis but no tumoral cells. A bone marrow biopsy was normal. A pleural puncture showed an exudative fluid (protein 50 g/l) with 9000 cells/mm3. Cytological and immunophenotypical analysis showed large cells with immunoblastic features, CD30−, CD38+, CD45+, human leukocyte antigen ABC+. Polymerase chain reaction demonstrated HHV-8 and EBV DNA in the pleural fluid and blood (Table 1). Because of the cirrhosis, cytostatic chemotherapy was delayed. Cidofovir (5 mg/kg every 14 days intravenously) and IFN-α (3 MIU, three times a week) were started in April 1998 in combination with HAART. His general condition improved rapidly. In June 98 the pleural and ascitic effusions had disappeared, and HHV-8 and EBV DNA were undetectable in the blood. Cidofovir was stopped in July 1998 and IFN-α in November 1998. In August 2000 the patient remained asymptomatic.Table 1: Follow-up of viral markers and treatments. HAART is thought to improve the prognosis of AIDS-related non-Hodgkin's lymphomas [1]. Because it is a rare disorder, little information is available about the benefit of HAART in the treatment of PEL. Oksenhendler et al. [2] reported one case of complete remission in a patient with two nucleoside inhibitors without cytostatic chemotherapy. As antiretroviral therapy is not active on EBV or HHV-8, the authors suggested that immune reconstitution and an indirect effect on the production of HIV proteins or cellular cytokines were likely to have improved their patient's condition. In vitro, HIV-infected cells induce HHV-8 lytic cycle replication in BCBL-1 cells (derived from PEL) and Kaposi's sarcoma cell growth, through the release of inflammatory cytokines or HIV gene products, in particular the Tat protein [3]. Moreover both reverse transcriptase nucleoside inhibitors and protease inhibitors prevent the induction of HHV-8 lytic replication and inhibit the spread of HHV-8 to uninfected cells when co-cultured with HIV [4]. On the other hand, Spina et al. [5] reported two cases in which HAART failed to control PEL: in one case HAART had only transient activity on the clinical symptoms and HHV-8 viral load, and in another case there was neither clinical nor viral benefit, despite the use of cytostatic chemotherapy. In our observation it was notable that PEL occurred 5 months after the beginning of HAART, despite good control of the HIV viral load, suggesting that HAART played no major role in the control of EBV and HHV-8 replication. By contrast, a dramatic decrease in the EBV and HHV-8 viral loads and long-term PEL remission was achieved rapidly after the start of cidofovir and IFN-α. In vivo, IFN-α is indicated for the treatment of cutaneous Kaposi's sarcoma, an HHV-8-associated malignancy. Moreover, IFN-α inhibits in-vitro HHV-8 reactivation in PEL cells and reduces the HHV-8 load in cultured peripheral blood mononuclear cells [6]. Cidofovir is a broad-spectrum antiviral drug and shows marked in-vitro activity against EBV and HHV-8 [7]. EBV is well known to have intrinsic cell transforming activity, and is strongly implicated in AIDS-related non-Hodgkin's lymphomas. Recently, Schmidt et al. [8] reported a beneficial effect of virostatic therapy (foscarnet) on EBV-associated polyclonal lymphoproliferation in an HIV-infected patient. Because tumoral cells are latently infected by HHV-8, it is likely that cidofovir may have only an indirect effect, if any, on HHV-8-infected tumoral cells. Nevertheless, recent reports [9,10] suggest that HHV-8 might have malignant transformation activity by itself, even in the absence of EBV and HIV co-infection. As previously reported for other HHV-8 and EBV-associated malignancies in HIV-infected patients, the association of broad-spectrum antiviral drugs and HAART should be considered as a potential treatment for HIV-related PEL, particularly when chemotherapy is contraindicated. Laurent Hocquelouxa Félix Agbalikab Eric Oksenhendlerc Jean-Michel Molinaa