AIDS-related non-Hodgkin Lymphoma Research Articles

Anti-retroviral treatment regimens and immune parameters in the prevention of systemic HIV-related non-Hodgkin's lymphoma

1034 Background: Immunosuppression induced by the human immunodeficiency virus (HIV) leads to an increased risk of non Hodgkin's lymphoma (NHL). We measured the influence of immunological factors and highly active antiretroviral therapy (HAART) regimes on this risk. As there are few data demonstrating that non nucleoside reverse transcriptase inhibitors (NNRTI) can protect from AIDS-defining illnesses, we compared different HAART regimens. Methods: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or NNRTIs on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also examined and entered in a univariate and multivariate analysis to establish risk of NHL. Results: 280 patients have been diagnosed with lymphoma including 206 with systemic NHL, 55 with primary cerebral lymphoma and 19 with Hodgkin's disease. During the HAART era (1996–2003), 5,832 individuals have been identified as being at risk of systemic NHL, representing a total of 34,133 patient years of follow up. Of these, 102 patients have been diagnosed with systemic HIV-related NHL. Univariate analysis demonstrated that increased age, higher nadir CD4 and CD8 T cell counts, CD19 B cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (p<0.05). In a multivariate analysis, age, nadir CD4 and CD8 T cell counts and exposure to HAART were independent predictors of risk of NHL (p < 0.02). NNRTI based HAART (adjusted rate ratio 0.4, 95% CI 0.3 to 0.5) had an identical protective effect to PI-based HAART and these were significantly more protective than nucleoside analogues alone (rate ratio 0.5, 95% CI 0.4 to 0.7) or no anti-retrovirals (p<0.001). Conclusions: HAART induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL. No significant financial relationships to disclose.

Anti-retroviral treatment regimens and immune parameters in the prevention of systemic HIV-related non-Hodgkin's lymphoma

1034 Background: Immunosuppression induced by the human immunodeficiency virus (HIV) leads to an increased risk of non Hodgkin's lymphoma (NHL). We measured the influence of immunological factors and highly active antiretroviral therapy (HAART) regimes on this risk. As there are few data demonstrating that non nucleoside reverse transcriptase inhibitors (NNRTI) can protect from AIDS-defining illnesses, we compared different HAART regimens. Methods: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or NNRTIs on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also examined and entered in a univariate and multivariate analysis to establish risk of NHL. Results: 280 patients have been diagnosed with lymphoma including 206 with systemic NHL, 55 with primary cerebral lymphoma and 19 with Hodgkin's disease. During the HAART era (1996–2003), 5,832 individuals have been identified as being at risk of systemic NHL, representing a total of 34,133 patient years of follow up. Of these, 102 patients have been diagnosed with systemic HIV-related NHL. Univariate analysis demonstrated that increased age, higher nadir CD4 and CD8 T cell counts, CD19 B cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (p<0.05). In a multivariate analysis, age, nadir CD4 and CD8 T cell counts and exposure to HAART were independent predictors of risk of NHL (p < 0.02). NNRTI based HAART (adjusted rate ratio 0.4, 95% CI 0.3 to 0.5) had an identical protective effect to PI-based HAART and these were significantly more protective than nucleoside analogues alone (rate ratio 0.5, 95% CI 0.4 to 0.7) or no anti-retrovirals (p<0.001). Conclusions: HAART induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL. No significant financial relationships to disclose.

Altered EBV viral load setpoint after HIV seroconversion is in accordance with lack of predictive value of EBV load for the occurrence of AIDS-related non-Hodgkin lymphoma.

In contrast to the situation in the post-transplant setting, in HIV-infected individuals an elevated EBV load is not predictive of EBV-related malignancies. To study whether a high EBV load is already a normal situation early in HIV infection and is not related to a decrease in immune function over time, we investigated EBV load and EBV-specific CD8(+) T cells approximately 1 year before and 1 year after HIV seroconversion. EBV load significantly increased after HIV seroconversion from 205 to 1002 copies/10(6) PBMC (p < 0.001), whereas no further increase in EBV load was observed between 1 and 5 years after HIV seroconversion (median, 1827-2478 copies/10(6) PBMC; p = 0.530). Interestingly, the absolute number of EBV lytic epitope, RAKFKQLL-specific CD8(+) T cells increased over HIV seroconversion (4.78 to 9.54/ micro l; p = 0.011). Furthermore, the fraction of CD27-negative effector, RAK-specific CD8(+) T cells tended to increase (from 12.2 to 17.31% CD27(-); p = 0.051), in accordance with Ag-driven differentiation. In conclusion, both virological and immunological data support the idea that a new EBV viral setpoint is reached early in HIV infection, probably by EBV reactivation, as suggested by the preferential increase in EBV lytic epitope-specific CD8(+) T cells. These data may thus help to explain the lack of predictive value of EBV load for the occurrence of AIDS-related lymphoma.

The evidence-based treatment of AIDS-related non-Hodgkin’s lymphoma

As we enter the third decade of the AIDS epidemic, it is apparent that a large number of cancers are more common in people with the human immunodeficiency virus type 1 (HIV). Non-Hodgkin’s lymphoma (NHL) remains the second most common tumour in such patients. At the onset of the epidemic, dose-intense combination regimens were used but these were quickly abandoned in favour of dose-modified strategies because of difficulties in tolerating aggressive chemotherapy in the presence of underlying immunosuppression. With the improvements in supportive care including more effective anti-retroviral therapies, colony-stimulating factors and prophylaxis against opportunistic infections, we are returning to the traditional chemotherapeutic approaches similar to those utilised in the non-HIV infected individual including infusional regimens. In this review, we discuss the evidence for choosing particular therapies in patients with AIDS-related NHL.

HIV Type 1 replication in cerebrospinal fluid of patients with AIDS-related non-Hodgkin's lymphoma receiving chemotherapy and antiretroviral therapy.

Chemotherapy for cancer could have negative effects on HIV-1 dynamic in addition to the effects on immunological status. At the moment few data are available about the effects of chemotherapy on systemic HIV-1 replication, but the effects on the central nervous system, considered an independent compartment for viral replication, has never been investigated. We studied 19 HIV-1-infected patients with non-Hodgkin lymphoma (NHL) treated concomitantly with chemotherapy and highly active antiretroviral therapy (HAART) to evaluate HIV-1 replication and assess virological response to HAART in cerebrospinal fluid during chemotherapy. No patients were diagnosed with lymphoma involvement of the central nervous system. In 18 of 19 patients an HIV-1 load below 200 copies/ml was obtained in cerebrospinal fluid (CSF) during treatment. A correlation between plasma and CSF HIV-1 RNA levels was present at baseline, and was confirmed at the fourth cycle of chemotherapy. A significant decline in the mean difference between plasma and CSF HIV-1 RNA load was observed when comparing the value at the first cycle of chemotherapy with subsequent cycles. HAART even during chemotherapy allows us to obtain an effective control of HIV-1 infection in CSF in patients affected by NHL. In HIV-infected patients with NHL, the contemporaneous administration of HAART and chemotherapy is advisable to obtain a suppression of HIV-1 replication in CNS compartment during the potentially immunosuppressing effect of cancer treatment.

AIDS-related Non-Hodgkin's Lymphoma: Etiology, Epidemiology, and Impact of Highly Active Antiretroviral Therapy

Lymphoproliferative disorders (LPD) occur more frequently in the immunosuppressed host compared to those who are immunocompetent. The biological and clinical characteristics of a particular LPD are specific to the underlying immune defect, though there are clear similarities in the various tumor types that occur. Immunosuppression-related LPD are more frequently associated with gammaherpesviruses suggesting that the immunologic environment influences tumorigenesis. Clinical outcomes may be optimized when appropriate treatment strategies are based on consideration of the underlying immunodeficiency and on the tumor biology. Consistent with this observation, in AIDS-related lymphomas (ARL), tumor biology, clinical presentations, and treatment outcomes are correlated with the CD4 cell count. This review will consider the role of immune deficiency in HIV disease on ARL pathogenesis and epidemiology, and the impact that highly active antiretroviral therapy has had in this disease.

Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma.

Objective: To evaluate clinicopathological features associated with leptomeningeal disease in systemic AIDS-related non-Hodgkin's lymphoma (NHL) and to compare outcomes to those without leptomeningeal disease. In addition to evaluate intrathecal chemoprophylaxis for patients with good immunological parameters and high risk of meningeal relapse (bone marrow, paraspinal or paranasal involvement or Burkitt's lymphoma histology).Design and methods: Prospective data, which has been collected on our cohort of 8640 HIV seropositive patients treated at the Chelsea and Westminster Hospital includes 176 patients with systemic AIDS-related NHL, was analysed.Results: At presentation, 18 (10%) patients had meningeal involvement. There were significant associations between meningeal disease and both Burkitt's lymphoma and paraspinal or paranasal involvement. There was no difference in the overall survival between patients with or without meningeal involvement at presentation (Kaplan-Meier log-rank, P = 0.35) and the I-year actuarial survivals are 25% [95% confidence interval (CI), 3-47%] for patients with meningeal involvement and 33% (95% Cl, 26-41%) for those without. Prophylactic intrathecal chemotherapy was administered to 21 high-risk patients and four (19%) relapsed with meningeal disease.Conclusions: This single-centre experience of a large cohort has demonstrated that meningeal involvement at presentation correlates with Burkitt's lymphoma histology and paraspinal or paranasal space disease, but not with bone marrow lymphoma. It also documents that long-term survival is achievable rarely in patients who present with meningeal disease and in patients with isolated meningeal relapse. (C) 2003 Lippincott Williams Wilkins.

Leptomeningeal disease in AIDS-related non-Hodgkin's lymphoma.

To evaluate clinicopathological features associated with leptomeningeal disease in systemic AIDS-related non-Hodgkin's lymphoma (NHL) and to compare outcomes to those without leptomeningeal disease. In addition to evaluate intrathecal chemoprophylaxis for patients with good immunological parameters and high risk of meningeal relapse (bone marrow, paraspinal or paranasal involvement or Burkitt's lymphoma histology). Prospective data, which has been collected on our cohort of 8640 HIV seropositive patients treated at the Chelsea and Westminster Hospital includes 176 patients with systemic AIDS-related NHL, was analysed. At presentation, 18 (10%) patients had meningeal involvement. There were significant associations between meningeal disease and both Burkitt's lymphoma and paraspinal or paranasal involvement. There was no difference in the overall survival between patients with or without meningeal involvement at presentation (Kaplan-Meier log-rank, P = 0.35) and the 1-year actuarial survivals are 25% [95% confidence interval (CI), 3-47%] for patients with meningeal involvement and 33% (95% CI, 26-41%) for those without. Prophylactic intrathecal chemotherapy was administered to 21 high-risk patients and four (19%) relapsed with meningeal disease. This single-centre experience of a large cohort has demonstrated that meningeal involvement at presentation correlates with Burkitt's lymphoma histology and paraspinal or paranasal space disease, but not with bone marrow lymphoma. It also documents that long-term survival is achievable rarely in patients who present with meningeal disease and in patients with isolated meningeal relapse.

Update on the Pathogenesis, Diagnosis, and Therapy of AIDS-related Lymphoma.

AIDS-related non-Hodgkin's lymphoma (ARL) is an opportunistic malignancy that foreshortens life more than any other commonly occurring HIV-associated cancer. Treatment strategies include low-dose chemotherapy, chemotherapy given with antiretroviral therapy, and infusional chemotherapy regimens. Rituximab, an anti-CD20 monoclonal antibody, has been found to be useful in non-HIV-associated lymphomas and is of interest in ARL as well. Since the advent of highly active antiretroviral therapy, the ARL incidence and survival has changed. This paper reviews the epidemiologic, biologic, and clinical features of ARL with the aim of presenting a cohesive overview of these elements.

Therapeutic Challenges of AIDS-Related Non-Hodgkin's Lymphoma in the United States and East Africa

Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. As we enter the third decade of the acquired immunodeficiency syndrome (AIDS) epidemic, it is apparent that the evolution of antiretroviral therapy and the emergence of combination antiviral strategies have greatly affected the natural history of HIV infection and its neoplastic complications. For example, there may be a trend for declining incidence of AIDS-related lymphoma in the United States for the first time. However, in regions of the world where the burden of HIV infection is greatest, such as in East Africa, AIDS-related lymphoma is an increasing cause of morbidity and mortality. Treatment of lymphoma has evolved coincident with improvements in antiretroviral therapy. Infusional chemotherapy regimens may offer advantages over other regimens and schedules, but comparative trials have not been done. Clinical trial data are available on which to develop therapeutic strategies to treat this disease in East Africa where pragmatic approaches are needed. Both the differences in manifestations of HIV infection and the inherent difficulties in administering cytotoxic chemotherapy in this part of the world must be taken into consideration in planning therapeutic strategies. Improved understanding of the pathogenesis of HIV infection and lymphoma will likely yield improved therapeutic interventions as well.

Characteristics and survival of patients with non-Hodgkin's lymphoma with and without acquired immunodeficiency syndrome.

Our objective was to determine the characteristics and survival of patients with non-Hodgkin's lymphoma (NHL) with and without acquired immunodeficiency syndrome (AIDS). A cancer registry and AIDS registry linkage for San Diego County was performed in October 1998 as part of a national multicentre study. We performed Kaplan-Meier analysis to compare survival in NHL patients with and without AIDS, after matching for age, sex, and race/ethnicity. We performed logistic regression to determine which patient and tumour characteristics were significantly associated with 1-year survival. Of the 4361 cases of NHL, 324 (7%) had AIDS and 4037 (93%) were not known to have AIDS. Patients with AIDS were more likely to have extranodal, high-grade, and disseminated NHL diagnosed by non-histologic means and were less likely to have received chemotherapy. Patients with AIDS and NHL who survived at least 1 year had less advanced disease stage and received chemotherapy. The median survival in patients with AIDS was 4 months (95% confidence interval (CI): 4-5) and 95 months (95% CI: 58-157) in patients without AIDS (P<0.001). Although these patients with AIDS-related NHL were unlikely to survive, the highly active antiretroviral agents currently used may improve outcomes in future patients.

AIDS-related systemic non-Hodgkin's lymphoma at a large community program.

The introduction of triple antiretroviral therapy has led to reductions in opportunistic diseases in HIV-infected patients. However, little is known of the effect of this therapy on the clinical and pathological features and the outcome of patients with AIDS-related systemic non-Hodgkin's lymphoma (NHL). We examined the incidence and clinical manifestations of HIV-infected patients with systemic NHL at the Harris County Hospital District and Veterans Affairs Medical Center (Houston, TX). Between January 1996 and December 2000, 76 cases of systemic NHL were diagnosed in 3655 HIV-infected patients. Three groups of patients diagnosed with systemic NHL were identified according to their history of antiretroviral therapy: treatment naive (n = 20), dual nucleoside (n = 22), and triple antiretroviral drug-treated patients (n = 34). The median duration of antiretroviral therapy before the diagnosis of systemic NHL in the triple antiretroviral and dual nucleoside treatment groups was 12 versus 8 months (p < 0.0004). Thirty-five percent of patients (12 of 34) in the triple treatment group had an HIV RNA viral load of <400 copies/ml and their median CD4+ cell count was 301 cells/mm(3) (range, 46 to 667 cells/mm(3)) at the time of diagnosis of systemic NHL. More patients treated with triple antiretroviral therapy received complete courses of chemotherapy as compared with the other two groups (p = 0.013). However, the overall survival did not differ significantly among the three groups of patients. These data suggest that AIDS-related systemic NHL continues to occur even in patients treated with triple antiretroviral therapy. In addition, this opportunistic malignancy is associated with significant mortality. Therefore, it is necessary to develop a better understanding of the pathogenesis of this disease.

Characteristics of indolent non‐hodgkin lymphoma in patients with type 1 human immunodeficiency virus infection

There is recent evidence that the incidence of indolent non-Hodgkin lymphoma (NHL) appears to be increased in persons with the acquired immunodeficiency syndrome (AIDS). The current study was conducted to describe the clinical, immunologic, and pathologic characteristics of indolent B-cell lymphoma in patients infected with the human immunodeficiency virus (HIV). The current report was a retrospective study of 10 cases of indolent NHL identified from the AIDS-Lymphoma Registry at the University of Southern California School of Medicine. These patients were compared with 336 consecutive patients with systemic intermediate/high-grade AIDS-related NHL who were diagnosed and treated at a single institution. The pathology of the indolent cases included follicular lymphoma (five patients), small lymphocytic lymphoma (two patients), and one case each of mucosa-associated lymphoid tissue (MALT), monocytoid B-cell, and marginal zone lymphoma. When comparing the indolent lymphomas with the intermediate/high-grade AIDS-NHL cases, no differences were observed with regard to demographic characteristics or history of prior opportunistic infection. HIV patients with indolent lymphomas were found to have a significantly higher median CD4+ lymphocyte count compared with patients with intermediate/high-grade NHL (531 /mm3 vs. 90 /mm3) (P < 0.0001). Bone marrow involvement was significantly more common in indolent NHL cases (50%) versus intermediate/high-grade NHL cases (17%) (P = 0.02). The median survival for patients with indolent NHL was significantly longer compared with patients with intermediate/high-grade NHL (66.8 months vs. 7.1 months) (P = 0.007). Indolent lymphomas occurring in patients infected with HIV appear to differ from intermediate/high-grade lymphomas with regard to immune status and propensity for bone marrow involvement and prolonged survival. The median survival in the group of HIV-seropositive patients with indolent NHL examined in the current study was found to be comparable to that reported in HIV-negative individuals.

AIDS-related non-Hodgkin's lymphoma: Clinico-pathological characteristics and therapeutic strategies (Review)

High-grade B-cell non-Hodgkin's lymphoma (NHL), a diagnostic disease for the acquired immunodeficiency syndrome (AIDS), is a late manifestation of HIV infection and is generally related to severe lymphopenia. We reviewed the main clinico-pathological features of this disease and analysed its pathogenetic mechanisms with potential therapeutic implications.

Detection of polyomavirus simian virus 40 tumor antigen DNA in AIDS-related systemic non-Hodgkin lymphoma.

Systemic non-Hodgkin lymphoma (S-NHL) is a common malignancy during HIV infection, and it is hypothesized that infectious agents may be involved in the etiology. Epstein-Barr virus DNA is found in <40% of patients with AIDS-related S-NHL, suggesting that other oncogenic viruses, such as polyomaviruses, may play a role in pathogenesis. We analyzed AIDS-related S-NHL samples, NHL samples from HIV-negative patients, peripheral blood leukocytes from HIV-infected and -uninfected patients without NHL, and lymph nodes without tumors from HIV-infected patients. Specimens were examined by polymerase chain reaction analysis with use of primers specific for an N-terminal region of the oncoprotein large tumor antigen ( T-ag ) gene conserved among all three polyomaviruses (simian virus 40 [SV40], JC virus, and BK virus). Polyomavirus T-ag DNA sequences, proven to be SV40-specific, were detected more frequently in AIDS-related S-NHL samples (6 of 26) than in peripheral blood leukocytes from HIV-infected patients (6 of 26 vs. 0 of 69; p =.0001), NHL samples from HIV-negative patients (6 of 26 vs. 0 of 10; p =.09), or lymph nodes (6 of 26 vs. 0 of 7; p =.16). Sequences of C-terminal T-ag DNA from SV40 were amplified from two AIDS-related S-NHL samples. Epstein-Barr virus DNA sequences were detected in 38% (10 of 26) AIDS-related S-NHL samples, 50% (5 of 10) HIV-negative S-NHL samples, and 57% (4 of 7) lymph nodes. None of the S-NHL samples were positive for both Epstein-Barr virus DNA and SV40 DNA. Further studies of the possible role of SV40 in the pathogenesis of S-NHL are warranted.

Detection of Polyomavirus Simian Virus 40 Tumor Antigen DNA in AIDS-Related Systemic Non-Hodgkin Lymphoma

Detection of Polyomavirus Simian Virus 40 Tumor Antigen DNA in AIDS-Related Systemic Non-Hodgkin Lymphoma

Multidrug resistance (MDR-1) expression in aids-related lymphomas

P-glycoprotein is a product of the multidrug resistance (MDR-1) gene. In non-Hodgkin's lymphoma, less than 20% of untreated de novo lymphomas express MDR-1 compared with approximately 50% after failure of chemotherapy. We wished to study the expression of MDR-1 in AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Tissue biopsies from 50 patients with newly diagnosed AIDS-NHL were studied by immunohistochemical analysis using C494, a monoclonal antibody specific for the MDR-1 isoform of P-gp. MDR-1 expression was correlated with patient demographics, lymphoma characteristics, response to chemotherapy, and survival. Forty-six males and four females with a median age of 38 years (range 26–63) were studied. A prior AIDS-defining opportunistic infection was reported in 35 patients (70%). The median CD4+ lymphocyte count was 69/mm 3 (range 0–920). Thirty-two patients (63%) had received prior anti-HIV therapy, including a protease inhibitor in five (10%). Pathologic types consisted of diffuse large cell in 13 (26%), immunoblastic in 13 (26%), small non-cleaved in 22 (44%), and high grade not otherwise specified in two (4%). The majority of patients (76%) had stage III/IV disease. Pre-treatment lymphoma tissues from 33 patients (66%) stained positively for MDR-1. MDR-1 positive patients had a significantly lower complete remission rate compared to MDR-1 negative patients (33 versus 65%, P=0.042). Duration of complete response was significantly longer in MDR-1 negative patients compared with MDR-1 positive patients (not reached versus 9.9 months, P=0.003). Strategies to overcome MDR-1 expression may be important for initial treatment in patients with AIDS-NHL.

High-Dose Cytosine–Arabinoside and Cisplatin Regimens as Salvage Therapy for Refractory or Relapsed AIDS-Related Non-Hodgkin's Lymphoma

No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP (n = 13) or with ESHAP (n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31 %) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.

Treatment of human immunodeficiency virus-related lymphoma

In newly diagnosed human immunodeficiency virus (HIV)-positive patients with non-Hodgkin's lymphoma (NHL), standard lymphoma regimens yield approximately a 50% complete response (CR) rate and an overall median survival of ≤9 months. Treatment results of relapsed patients are extremely poor. Regimens that appear more effective than standard therapy have usually been investigated only in patients with relatively high CD4 counts. An exception is a regimen consisting of a continuous 96-hour infusion of cyclophosphamide, doxorubicin, and etoposide (CDE). A 62% CR rate was achieved in 21 patients with a median CD4 count of 87/μL, and the median overall survival was 18 months. In another study of 25 patients, didanosine (ddl) was added to CDE and was shown to cause less myelosuppression without compromising efficacy. Other studies suggest that highly active antiretroviral therapy (HAART) can be combined with intensive chemotherapy regimens, with improved efficacy attributed to less frequent dosage reduction of chemotherapeutic agents. More recently, autologous and syngeneic bone marrow transplantation have been explored in a handful of patients with acquired immunodeficiency syndrome (AIDS)-related NHL with promising results. Data on whether widespread use of HAART decreases the incidence of HIV-positive NHL are conflicting. Some clues from recent studies suggest we are close to an answer: (1) protease inhibitors significantly improve survival of HIV-positive patients with NHL; (2) only one of eight recent cases of HIV-positive men with NHL received HAART compared with greater than 70% of HIV-positive men free of NHL; and (3) no prior HAART independently predicted for AIDS-related NHL development. On the other hand, Hodgkin's disease may be increasing in frequency in HIV-positive patients as the incidence of NHL declines. It is hypothesized that more effective reconstitution of the immune system with HAART may facilitate the inversion of these incidences. Future prospective studies will hopefully answer these questions.

Dysfunctional Epstein-Barr virus (EBV)–specific CD8+T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma

AbstractAcquired immunodeficiency syndrome–related non-Hodgkin lymphomas (AIDS-NHL) are thought to arise because of loss of Epstein-Barr Virus (EBV)-specific cellular immunity. Here, an investigation was done to determine whether cellular immunity to EBV is lost because of physical loss or dysfunction of EBV-specific cytotoxic T cells. Data on EBV-specific cellular immunity were correlated with EBV load. For comparison, individuals who progressed to AIDS with opportunistic infections (AIDS-OI) and long-term asymptomatics (LTAs) were studied. The number of virus-specific T cells was detected using tetrameric HLA–EBV-peptide complexes; function of these EBV-specific T cells was determined using the interferon-γ (IFN-γ) Elispot assay. It was observed that EBV-specific CD8+ T cells were present in normal numbers in human immunodeficiency virus (HIV)-infected individuals. However, their functional capacity was decreased compared with HIV− individuals. In AIDS-NHL patients, EBV-specific T cells were not physically lost in the course of HIV-1 infection but showed progressive loss of their capability to produce IFN-γ in response to EBV peptides. This loss of function correlated with lower CD4+ T-cell numbers and was accompanied by increasing EBV load. In HIV-1–infected LTA individuals, in whom CD4+T-cell numbers were maintained, and progressors to AIDS-OI, IFN-γ–producing EBV-specific T cells were stable and EBV load remained stable or decreased in the course of HIV infection, suggestive of immune control. Our data indicate that functional loss of EBV-specific CD8+ T cells with a concomitant increase in EBV load may play a role in the pathogenesis of AIDS-NHL.