Absolute level of Epstein-Barr virus DNA in human immunodeficiency virus type 1 infection is not predictive of AIDS-related non-Hodgkin lymphoma

To study whether Epstein-Barr virus (EBV) load can be used to predict the occurrence of acquired immunodeficiency syndrome-related non-Hodgkin lymphoma (AIDS-NHL), we determined EBV load longitudinally for individuals infected with human immunodeficiency virus type 1. EBV load in peripheral blood mononuclear cells (PBMC) was high and displayed considerable fluctuations over time, indicating that absolute EBV load in PBMC is not predictive of the development of AIDS-NHL. EBV DNA was also detectable in serum at some time points but at a lower level.     

Coinfection with multiple strains of the Epstein-Barr virus in human immunodeficiency virus-associated hairy leukoplakia.

Epstein-Barr virus DNA was analyzed from specimens of hairy leukoplakia, an oral lesion that occurs in patients infected with the human immunodeficiency virus. The simultaneous presence of both type 1 and type 2 Epstein-Barr virus was demonstrated by Southern blot analysis and polymerase chain reaction assay. Restriction fragment length polymorphisms in the BamHI WYH region and in clones of the EcoRI C region suggested the presence of multiple strains of type 1 and type 2 viruses. The demonstration of multiple variably sized BamHI H fragments on Southern blot analysis and cloning of the EBNA-2 gene coding region also suggested the presence of multiple viral strains or variants coinfecting hairy leukoplakia. Recombination of the viral genome in and around the EBNA-2 gene apparently generated viral variants that replicated efficiently, one of which appeared to increase in abundance in a lesion over time. These data indicate that hairy leukoplakia involves coinfection with multiple strains of replicating Epstein-Barr virus and the endogenous generation of viral variants, some of which have mutations of the EBNA-2 gene.     

Response-adapted therapy with infusional EPOCH chemotherapy plus rituximab in human immunodeficiency virus-associated,B-cell non-Hodgkin lymphoma

Four cycles of rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy is as effective as six cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with human immunodeficiency virus-associated DLBCL and high-grade lymphoma treated with four to six cycles of EPOCH plus rituximab based on a response-adapted treatment strategy. One hundred and six evaluable patients with human immunodeficiency virus-associated DLBCL or highgrade CD20⁺ non-Hodgkin lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by an intravenous bolus of cyclophosphamide every 21 days for four to six cycles. Patients received two additional cycles of therapy after documentation of a complete response by computed tomography after cycles 2 and 4. Sixty-four of 106 evaluable patients (60%; 95% confidence interval [95% CI]: 50%-70%) in both treatment arms had a complete response. The 2-year event-free survival rates were similar in the 24 patients with complete response who received four or fewer cycles of EPOCH (78%; 95% CI: 55%-90%) due to having achieved a complete response after two cycles, compared with those who received five or six cycles of EPOCH (85%; 95% CI: 70%-93%) because a complete response was first documented after cycle 4. A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in patients with human immunodeficiency virus-associated lymphoma treated with EPOCH plus rituximab, which merits further evaluation in additional prospective trials. Clinical Trials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00049036","term_id":"NCT00049036"}}NCT00049036.     

Epstein-Barr virus-associated Hodgkin's lymphoma

Survivors of Hodgkin's lymphoma (HL) frequently have many years to experience the long-term toxicities of combined modality therapies. Also, a significant proportion of HL patients will relapse or have refractory disease, and less than half of these patients will respond to current salvage strategies. 30-50% of HL cases are Epstein-Barr virus associated (EBV-positive HL). The virus is localized to the malignant cells and is clonal. EBV-positive HL is more frequent in childhood, in older adults (>45 years) and in mixed cellularity cases. The survival of EBV-positive HL in the elderly and the immunosuppressed is particularly poor. Despite improvements in our understanding of EBV-positive HL, the true contribution of EBV to the pathogenesis of HL remains unknown. Increased knowledge of the virus' role in the basic biology of HL may generate novel therapeutic strategies for EBV-positive HL and the presence of EBV-latent antigens in the malignant HL cells may represent a target for cellular immunotherapy.     

Epstein-Barr virus-related oral T-cell lymphoma associated with human immunodeficiency virus immunosuppression

Epstein-Barr virus (EBV) is generally held to infect B cells and epithelial cells, although there are now reports of EBV infection in normal T cells and neoplastic T-cell diseases. In patients with human immunodeficiency virus (HIV) infection, EBV is associated with the benign epithelial lesion, hairy leukoplakia, and has been reported in up to 80% of acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma. This study shows the presence of EBV in malignant oral T-cell lymphoma in three AIDS patients, two of whom had concurrent manifestation of hairy leukoplakia. The T-cell lineage of the tumor cells was determined by positive immunophenotyping for T-cell markers and lack of B-cell or nonhematopoietic (cytokeratin) determinants. All tumors contained monoclonal T-cell populations shown by polymerase chain reaction, which showed amplification of T-cell receptor gamma chain DNA without evidence of Ig heavy chain gene rearrangement. Furthermore, these lesions showed the presence of EBV DNA and expression of EBV latent gene products in the tumor cells. EBV involvement in AIDS-related T-cell lymphoma has not been widely reported and may represent a further manifestation of opportunistic EBV infection arising in the HIV-immunocompromised host.     

Epstein-Barr virus-associated lymphoma in Crohn's disease

Although no increased risk of developing lymphoproliferative disorders has been observed in population-based studies of patients with Crohn's disease, the possibility has been suggested in the subset of patients previously treated with thiopurine metabolites and suffering from concomitant Epstein-Barr virus infection. A few cases of lymphomas have occurred in patients with Crohn's disease treated with infliximab, only one of whom showed the presence of the Epstein-Barr virus genome. We here describe the case of a patient with steroid-dependent ileal Crohn's disease treated with azathioprine and a single infusion of infliximab, who developed a diffuse large B cell ileal lymphoma. Epstein-Barr virus genome was detected in the neoplastic cells by means of polymerase chain reaction. Epstein-Barr virus may be detected in the neoplastic tissues of lymphomas of patients with Crohn's disease treated with immunosuppressants and infliximab. The identification of such cases may help to define the frequency of this association and how to manage the lymphoproliferative disorder.     

T-cell non-Hodgkin lymphoma in human immunodeficiency virus-1-infected individuals

We present two patients with human immunodeficiency virus-1 (HIV-1) infection in whom T-cell non-Hodgkin lymphoma developed, based on pathologic diagnosis, immunophenotyping, and T-cell receptor gene rearrangement. Both cases were positive for human immunodeficiency virus-1 by enzyme-linked immunosorbent assay and immunoblot methods. Histologic sections from each patient showed a high-grade pleomorphic T-cell non-Hodgkin lymphoma, and immunophenotyping demonstrated a prevalence of reactivity for CD4 (helper) over CD8 (suppressor) antigens. T-cell receptor beta-chain gene rearrangement studies revealed a rearranged pattern with either the HindIII or BamHI enzymes, whereas immunoglobulin heavy chain genes retained a germ-line configuration. Viral sequences specific for human T-cell leukemia virus-I, human T-cell leukemia virus-II, or HIV-1 were not detected. Thus, although rare, T-cell non-Hodgkin lymphoma may be observed in HIV-1-infected individuals.     

Clinical characteristics of human immunodeficiency virus-associated Hodgkin lymphoma patients in Japan

The incidence of Hodgkin lymphoma (HL) is paradoxically increasing in the combination anti-retroviral therapy (cART) era. However, there has been no nationwide survey of human immunodeficiency virus (HIV)-associated HL (HIV-HL) in Japan. We retrospectively examined the clinical characteristics and outcomes of 19 newly diagnosed HIV-HL patients at 11 HIV/AIDS and hematology regional hospitals in Japan between 1991 and 2010. At the time of HL diagnosis, 79?% of patients were receiving cART. All the patients, but one received HL diagnoses in the cART era. The median CD4+ cell count at HIV-HL diagnosis was 169/μl. Mixed-cellularity classical Hodgkin lymphoma was the most common subtype occurring in 68?% of the patients; 89?% of the patients were positive for Epstein-Barr virus. Of these 19 patients, 84?% were in advanced stages, with bone marrow involvement observed in 47?% of the patients; 58?% had extranodal sites. All the treated patients were given cART concurrent with HL therapy. The complete remission rate of the treated patients was 87?%. The median OS of the entire cohort was 17?months. These results suggest that the characteristics of HIV-HL in Japan are more aggressive than those of non-HIV-associated HL in Japan, but standard chemotherapy is effective and feasible.     

Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma.

The Epstein-Barr virus (EBV) is associated with distinct forms of human lymphoid malignancies, including the endemic (eBL) and sporadic forms of Burkitt's lymphoma (sBL) and acquired immunodeficiency syndrome-associated non-Hodgkin lymphoma (AIDS-NHL). However, whether EBV has a pathogenetic role in these tumors or is a passenger virus has not been conclusively demonstrated. One element to distinguish between these two possibilities is to determine whether EBV infection has preceded and, thus, possibly contributed to clonal expansion, or whether infection has occurred after clonal expansion and thus is unlikely to contribute to pathogenesis. Toward this end we analyzed the structure of the heterogeneous genomic termini of EBV as markers of clonal infection in a panel of eBL (11 cases), sBL (9 cases), and AIDS-NHL (10 cases) biopsies. We show that EBV termini are uniformly clonal in sBL, eBL, and AIDS-NHL, strongly suggesting that EBV infection has preceded and, thus, most likely contributed to clonal expansion in these malignancies.     

Epstein-Barr virus-associated bronchial leiomyoma in a boy with cellular immunodeficiency

Bronchial leiomyoma is a rare disease in children. Recently, the association of leiomyoma and HIV infection was reported. We describe a boy with a cellular immunodeficiency, who had endobronchial leiomyoma. The tumor cells were positive for Epstein-Barr virus-encoded RNA-1 (EBER-1) and Epstein-Barr virus-determined nuclear antigen-2, suggesting a role of Epstein-Barr virus in the pathogenesis of leiomyoma.     

Case of Epstein-Barr virus-associated transformation of mantle cell lymphoma

We report here a case of mantle cell lymphoma (MCL) in a patient who, following Epstein-Barr virus (EBV) infection, developed diffuse large B-cell lymphoma (DLBCL). A 47-year-old woman was diagnosed as having MCL with clinical stage IIIA in July 1990. After treatment with a third-generation chemotherapy without response, she was kept under observation for 8 years. In January 1999, fever and night sweats appeared with laboratory evidence for EBV infection, and acute swelling of lymph nodes and hepatosplenomegaly developed in May 1999. Histopathological examination confirmed the diagnosis of DLBCL. Sequence analysis of the complementarity-determining region (CDR)-III of the immunoglobulin heavy chain gene demonstrated clonal identity between the initial MCL and the subsequent DLBCL. Immunohistochemistry revealed that cyclin D1, CD5, and CD20 were expressed in the MCL but lost in the DLBCL cells, and EBER-ISH confirmed that EBV infection was absent in the former but present in the latter. Southern hybridization with the EBV terminal repeat probe showed a clear monoclonal pattern in the DLBCL specimen. All these results suggest that EBV infection may have been the molecular event that caused transformation of MCL cell(s) to DLBCL in this case. This is, to the best of our knowledge, the first well-documented case of EBV-associated transformation of MCL.     

High frequency of human immunodeficiency virus-associated autonomic neuropathy and more severe involvement in advanced stages of human immunodeficiency virus disease.

We conducted a controlled trial to determine frequency and severity of autonomic neuropathy in patients infected with the human immunodeficiency virus (HIV). We studied 25 HIV-seropositive patients and 10 seronegative controls in HIV risk groups by means of five cardiovascular tests, and autonomic neuropathy was graded with a scoring system. The overall autonomic test score differed between patients and controls and was higher in patients with advanced (Centers for Disease Control class IV) disease than in those with earlier (class II or III) HIV disease. Of the patients, 60% had findings of autonomic dysfunction. Our data demonstrate a high prevalence of autonomic neuropathy in HIV-infected patients. Advanced HIV disease is associated with more severe involvement than earlier disease states.     

Human immunodeficiency virus-associated malignant lymphoma in eastern Denmark diagnosed from 1990-1996: clinical features, histopathology, and association with Epstein-Barr virus and human herpesvirus-8

The clinicopathological features of human immunodeficiency virus (HIV)-associated lymphoma were investigated in a retrospective study of 85 adult patients in eastern Denmark diagnosed during the period 1990-1996. The possible pathogenetic role of Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) in these tumours was also studied. Seventy patients (82%) presented with extranodal disease and 26 (31%) had CNS involvement at diagnosis. Diffuse large cell B-cell lymphoma was the most frequent histological subtype, comprising 65 of 79 cases available for microscopic re-evaluation (82%) and including 20 of 23 evaluable patients with CNS lymphoma (87%). EBV RNA was demonstrated by in situ hybridization in 51 of 65 evaluable tumours (79%) and in 14 of 16 cases (88%) with CNS-lymphoma. Three cases showed a T-cell phenotype. The presence of HHV-8 DNA was analysed by PCR in 32 cases. A strong band consistent with tumour cell infection was detected in only one case, weaker bands being seen in 4 cases. None of these patients had primary effusion lymphomas. In conclusion, Danish AIDS-related lymphomas are of predominantly high-grade B-cell type with extranodal localization and atypical presentation. Our results provide further evidence that EBV plays a major role in the pathogenesis of large cell AIDS-related lymphoma, whereas HHV-8 does not appear to contribute significantly to the development of solid lymphomas in this group of patients.