Epstein‐ B arr virus load in plasma is an early biomarker of HIV ‐related lymphomas

Abstract

Background: Epstein Barr virus (EBV) has been detected in the tumor cells of some non-Hodking lymphomas (NHL) and Hodgkin lymphomas (HL) and detectable EBV loads have been found in the plasma of immunocompetent patients with HL. In HIV-related lymphomas the importance of EBV load as potential lymphoma biomarkers has been scarcely studied. Aims: We aimed to evaluate the usefulness of EBV load in plasma as lymphoma biomarker in HIV-infected patients. Methods: One hundred and fifteen patients with NHL (HIV-infected =57 and HIV-uninfected=34) and HL (HIV-infected= 16 and HIV-uninfected= 8) were studied. EBV loads were determined in plasma by means of a commercial realtime PCR technique (EBV PCR kit, Qiagen GmbH, Hilden, Germany) at lymphoma diagnosis and in a group of HIV-infected patients also at one year before diagnosis (N=11) and at complete response (CR) (N=34). EBER expression was studied by in situ hybridization in tumor biopsies. The following clinical and biological parameters were collected from records: age, gender, date of lymphoma diagnosis, ECOG score, extranodal and bulky disease, B symptoms, Ann-Arbor stage, serum lactate dehydrogenase and beta2-microglobulin, International Prognostic Index (IPI), HCV and HBV serology, history of opportunistic infection and of AIDS-defining illness, onset of combination antiretroviral therapy, CD4-counts, HIV loads, type and date of response, relapse date, last follow up or death date. McNemar's test and Wilcoxon test were used to compare quantitative and qualitative variables, respectively. Survival analyses were performed using the Kaplan-Meier method. P-values of less than 0.05 were considered statistically significant. (Figure presented). Results:At diagnosis, EBV loads were detectable in more HIV-infected patients than HIV-uninfected (48% vs 14%, P=0.002) and in more HL cases than NHL (70% vs 26.3%, P=0.006). In HIV-infected patients, detectable EBV load was associated with EBER expression, 66.6% of the patients with detectable EBV loads had EBER-positive tumors and 92% of the patients with undetectable EBV loads had EBER-negative tumors (P=0.003). All the remaining clinical and biological features were not associated with detectable EBV load in plasma. In HIV-uninfected patients, associations between EBV load and EBER expression (P=0.006) and EBV load and HBV infection (P=0.017) were observed. From 16 out of 34 (47%) HIV-infected patients with detectable EBV loads at lymphoma diagnosis, 15 had undetectable EBV loads at CR (P<0.001) (Figure 1). The exception was one patient with HL whose EBV load substantially decreased at CR but was still detectable. Moreover, 4 out of 7 HIV-infected patients with detectable EBV loads at diagnosis had detectable loads one year before diagnosis, and no patient with negative EBV loads at diagnosis had detectable loads before it, pointing EBV load can be used as an early biomarker of lymphoma. EBV loads at diagnosis had neither impact on overall survival nor progression- free survival. Summary/Conclusions: EBV-load in plasma can be used as early biomarker of lymphoma in HIV-infected patients since EBV-loads can be detected up to 1 year before lymphoma diagnosis and are virtually undetectable at lymphoma CR.