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In HIV-seronegative patients with advanced Hodgkin lymphoma (HL), Epstein-Barr virus (EBV) viraemia at diagnosis predicts a worse progression-free survival (PFS), independent of the International Prognostic Score. However, its role in HIV-associated HL is uncharacterised. We collected clinico-pathologic and treatment data from a prospective series of 44 HIV-associated HLs from 2000 to 2016. We evaluated circulating EBV DNA as a prognostic factor on uni- and multivariable analyses in relationship to the International Prognostic Index criteria. In 44 patients with HIV-associated HL, EBV was detected by in situ hybridisation in all diagnostic biopsies. Blood EBV DNA was detectable in 26 patients (59%) with a median of 600 copies/mL (range 0-161,000). EBV DNA was independent of CD4 cell count (p = 0.9) or HIV viral load (p = 0.6) and did not predict PFS (HR 1.6, 95% CI 0.39-6.7, p = 0.49). EBV DNA is not a prognostic trait in HIV-associated HL. Prognostication in HIV-associated HL should be solely based on the International Prognostic Index criteria.

Introduction: The emergence of combined antiretroviral therapy (cART) and improvements in the management of opportunistic infections have altered the HIV epidemic over the last 30 years. We aimed to assess changes to the biology and outcomes of HIV-associated lymphomas over this period at the national center for HIV oncology in the United Kingdom., Methods: Clinical characteristics at lymphoma diagnosis have been prospectively collected since 1986, along with details of lymphoma treatment and outcomes. The clinical features and outcomes were compared between 3 decades: pre-cART decade (1986-1995), early-cART decade (1996-2005), and late-cART decade (2006-2015)., Results: A total of 615 patients with HIV-associated lymphoma were included in the study: 158 patients in the pre-cART era, 200 patients in the early-cART era, and 257 patients in the late-cART era. In more recent decades, patients were older (P < 0.0001) and had higher CD4 cell counts (P < 0.0001) at lymphoma diagnosis. Over time, there has also been a shift in lymphoma histological subtypes, with an increase in lymphoma subtypes associated with moderate immunosuppression. The overall survival for patients with HIV-associated lymphoma has dramatically improved over the 3 decades (P < 0.0001)., Conclusion: Over the last 30 years, the clinical demographic of HIV-associated lymphomas has evolved, and the outcomes have improved.

Background: The treatment and outcomes of patients with human immunodeficiency virus (HIV)-associated Hodgkin lymphoma (HL) continue to evolve. The International Prognostic Score (IPS) is used to predict the survival of patients with advanced-stage HL, but it has not been validated in patients with HIV infection., Methods: This was a multi-institutional, retrospective study of 229 patients with HIV-associated, advanced-stage, classical HL who received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus combination antiretroviral therapy. Their clinical characteristics were presented descriptively, and multivariate analyses were performed to identify the factors that were predictive of response and prognostic of progression-free survival (PFS) and overall survival (OS)., Results: The overall and complete response rates to ABVD in patients with HIV-associated HL were 91% and 83%, respectively. After a median follow-up of 5 years, the 5-year PFS and OS rates were 69% and 78%, respectively. In multivariate analyses, there was a trend toward an IPS score >3 as an adverse factor for PFS (hazard ratio [HR], 1.49; P=.15) and OS (HR, 1.84; P=.06). A cluster of differentiation 4 (CD4)-positive (T-helper) cell count <200 cells/μL was associated independently with both PFS (HR, 2.60; P=.002) and OS (HR, 2.04; P=.04). The CD4-positive cell count was associated with an increased incidence of death from other causes (HR, 2.64; P=.04) but not with death from HL-related causes (HR, 1.55; P=.32)., Conclusions: The current results indicate excellent response and survival rates in patients with HIV-associated, advanced-stage, classical HL who receive ABVD and combination antiretroviral therapy as well as the prognostic value of the CD4-positive cell count at the time of lymphoma diagnosis for PFS and OS., (© 2014 American Cancer Society.)

Purpose: The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL., Patients and Methods: From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS≥3: 68% v 26%, respectively; P<.001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy., Results: The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P=not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P=not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P=not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status., Conclusion: This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS.

Background: Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell lymphoma strongly associated with human immunodeficiency virus (HIV) infection. The authors conducted a multi-institutional, retrospective study to describe characteristics and determine prognostic factors in HIV-associated PBL., Methods: For this study, the investigators included consecutive, HIV-positive patients diagnosed between the years 2000 and 2010 whose tumors had a plasmablastic morphology, were cluster of differentiation 20 (CD20)-negative, and expressed markers of plasmacytic differentiation., Results: Fifty patients from 13 institutions were evaluated. The median age was 43 years, and there was a male predominance. The median count of cells that were positive for CD4 (a glycoprotein expressed on the surface of T-helper cells, monocytes, macrophages, and dendritic cells) was 206 cells/mm(3) . At presentation, 90% of patients had extranodal involvement, 69% presented with advanced stage disease, and 27% had oral involvement. Rearrangements of v-myc myelocytomatosis viral oncogene homolog (MYC) were detected in 41% of the tested patients. Eighty-five percent of patients received chemotherapy, with 63% receiving cyclophosphamide, doxorubicin, vincristine, and prednisone and 37% receiving more intensive regimens. The complete response (CR) rate was 66%. The median overall survival (OS) was 11 months regardless of the intensity of chemotherapy. In the survival analysis, an Eastern Cooperative Oncology Group performance status ≥2, advanced stage, and MYC rearrangements were associated significantly with a worse outcome, whereas attaining a CR with chemotherapy was associated with a better outcome., Conclusions: The prognosis of PBL in HIV-infected individuals remains poor in the highly active antiretroviral therapy era. Intensive chemotherapy regimens do not seem to increase survival in patients with HIV-associated PBL. Cancer 2012., (Copyright © 2012 American Cancer Society.)

Background: Interim PET scans in HIV-negative patients with Hodgkin lymphoma has emerged as one of the most important prognostic tools. However, equivalent studies in HIV-positive patients are yet to be performed., Objective: We evaluated the prognostic value of interim [18F]-fluoro-2-deoxy-D-glucose-PET (18F-FDG PET) after two or three cycles of chemotherapy using adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) with concomitant HAART in HIV-positive patients with Hodgkin lymphoma., Methods: Patients with advanced HIV-Hodgkin lymphoma (HIV-HL) from six UK centres were included. Interim PET scans after two or three cycles of ABVD (PET-2 or PET-3) were carried out. Prognostic analysis correlated the 2-year progression-free survival (PFS) rate with the interim PET result., Results: Twenty-three evaluable patients were assessed, 21 achieved a negative interim PET and 22 achieved complete remission by computerized tomography scan criteria after ABVD therapy. After a median follow-up of 27 months (range 12-50), disease progression was seen in one patient. Treatment failure was seen in one of the two interim PET-positive patients and none of the interim PET-negative patients. The 2-year PFS for interim PET-positive patients was 50%, and 100% for interim PET-negative patients (P = 0.0012)., Conclusion: A negative interim 18F-FDG PET result is highly predictive of treatment success in HIV-HL patients.

Purpose: To describe clinical features, treatment outcomes and relapse rates in HIV-associated multicentric Castleman's disease (MCD) in a sizeable mature cohort., Methods: From a prospective database, we identified 61 HIV-seropositive patients with histologically confirmed MCD (median follow-up, 4.2 years). Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide., Results: At MCD diagnosis, 55 (90%) of 61 patients met proposed clinical criteria defining an attack. Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years. With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001). Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD. Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission. The 2- and 5-year progression-free survival rates for all 49 patients treated with rituximab-based therapy were 85% (95% CI, 74% to 95%) and 61% (95% CI, 40% to 82%), respectively., Conclusion: HIV-associated MCD is a remitting-relapsing disease. The outlook has improved dramatically in recent years with the introduction of rituximab-based therapy and yields high overall survival rates.

HIV infection has been associated with an increased risk of developing several types of malignancies, including aggressive peripheral T-cell lymphomas (PTCL). However, this is a rare occurrence with no more than a hundred cases reported in the literature. The purpose of this multicenter study is to describe the characteristics and to identify prognostic factors in patients with HIV-associated PTCL. Data from HIV-positive patients with a pathological diagnosis of non-primary cutaneous, non-leukemic PTCL were gathered retrospectively and are reported using descriptive statistics. Univariate and multivariate survival analyses were also performed. Fifty one patients were included in our analysis. Median age was 38 years with a 5:1 male-to-female ratio. Patients presented with a median CD4(+) count of 173 cells mm⁻³, and a median HIV viral load of 334,787 copies ml⁻¹. The median time from HIV diagnosis to PTCL diagnosis was 4.5 years. About 75% of patients presented with advanced clinical stage and 66% with B symptoms. The most common subtypes were PTCLU (61%) and anaplastic large cell lymphoma (ALCL, 22%). None of the ALCL patients tested expressed ALK. The median overall survival (OS) for the group was 12 months. In the multivariate survival analysis, the use of HAART and patients' performance status were independently associated with OS. HIV-associated PTCL presents predominantly in young men with low CD4(+) counts and high HIV viral loads. Both HIV-related and lymphoma-related factors were associated with OS., (Copyright © 2011 Wiley-Liss, Inc.)

Objective and Design: : To retrospectively describe the recovery of cellular immunity and the clinical outcome of 30 patients with HIV-associated Burkitt's lymphoma (HIV-BL), who were treated with the intensive chemotherapy CODOX-M/IVAC and HAART as part of their standard care., Patients and Methods: : Seventy-three percent of the patients had high-risk disease, defined by stage, performance status, extranodal sites and lactate dehydrogenase. The median CD4 cell count at diagnosis of HIV-BL was 171/ml (range: 4-848) and the plasma HIV viral load was undetectable in five of 29 patients., Results: : Nine patients died during treatment (disease progression, three; toxicity, five; central nervous system lesion not biopsied, one). Response rate was 70% (complete response/complete response uncertain, 17; partial response, 4). After a median follow-up of 22 months (range: 6-72), 18 patients remain alive without disease progression. The 3-year overall survival and event-free survival were 52 and 75%, respectively. Viral load was undetectable in 88% and CD4 cell count more than 200/ml in 58% of patients assessed 6 months after completing chemotherapy, and in 87 and 80% at 12 months, respectively., Conclusion: : The intensive regimen CODOX-M/IVAC, a feasible and effective chemotherapy, is associated with an excellent immunological recovery in patients with HIV-BL on HAART.

The onset of the AIDS epidemic in 1981 was followed by descriptions of many opportunistic infections as well as several unusual cancers. Non-Hodgkin's lymphoma (NHL) was classified as an AIDS-defining illness within 4 years, and is up to 200 times more common in HIV-positive patients. Immunotherapy for cancer has a surprisingly long heritage, but it is only recently that this approach has become established in oncology practice. Here, against a background of the history of immunotherapy, we review clinicopathological features of HIV-associated NHL and discuss current cancer immunotherapeutic treatments including immune reconstitution using highly active antiretroviral therapy (HAART), anti-CD20 monoclonal antibodies, radioimmunotherapy, stem cell transplantation, cytokine therapy and vaccination. As the prognosis for HIV-associated NHL nears that of the general population, these approaches are of increasing importance and value.

Since the introduction of highly active antiretroviral therapy, there has been a decline in the incidence of non-Hodgkin's lymphoma among HIV-infected individuals. We described trends in the incidence of systemic non-Hodgkin's lymphoma in the UK CHIC Study from 1996-2006 and evaluated the association between immunosuppression and development of systemic non-Hodgkin's lymphoma: 286/23,155 (1.2%) individuals developed an AIDS-defining lymphoma (258 systemic). Younger age, receipt of highly active antiretroviral therapy and later calendar year were all independently associated with a reduced risk of systemic non-Hodgkin's lymphoma. A lower latest CD4 count was strongly associated with systemic non-Hodgkin's lymphoma, in patients who had (RR per log(2)(cells/mm(3)) higher: 0.62) and had not (0.70) received highly active antiretroviral therapy. Associations with other measures of immunosuppression, including nadir CD4 count, experience and duration of severe immunosuppression, were generally weaker. Earlier highly active anti-retroviral therapy initiation and wider access to HIV testing is advocated to reduce the risk of systemic non-Hodgkin's lymphoma.

The late effects of chemotherapy on immunologic parameters in AIDS-related non-Hodgkin lymphoma (NHL) have not been described. From a cohort of 105 consecutive patients treated with infusional chemotherapy and highly active antiretroviral therapy (HAART), 68 survived more than 3 months following the end of chemotherapy. Their lymphocyte subsets and plasma HIV viral loads were measured at regular intervals for 2 years and values compared with baseline. During chemotherapy, there were statistically significant falls in CD4 (helper T), CD8 (cytotoxic T), and CD19 (B) cell populations but no changes in the CD56 (natural killer [NK]) cell population. Among the 68 survivors, there were statistically significant increases in CD4, CD8, CD19, and CD56 cell populations during the first year of follow up, compared with the values at the start of chemotherapy. During the second year of follow up, there were further statistically significant rises in CD4 and CD19 cell populations, compared with the values at 12 months after chemotherapy. During 244 years of follow-up since chemotherapy in these 68 survivors, 7 second primary tumors and 8 opportunistic infections were diagnosed. Chemotherapy and concomitant HAART for AIDS-related NHL does not cause prolonged suppression of lymphocyte subsets. These data should provide reassurance regarding the long-term consequences of chemotherapy in these individuals.

A 44-year-old man with relapsed HIV-associated stage IV nodular sclerosing Hodgkin's disease underwent high-dose therapy with autologous stem cell transplantation. The transplant was uncomplicated and the patient remains in complete remission at 59 months. Autologous stem cell transplantation is safe in HIV patients and can achieve long-term durable remissions in Hodgkin's disease.

Background and Purpose: AIDS-related systemic non-Hodgkin lymphoma (ARL) remains a significant cause of morbidity and mortality in patients infected with the human immunodeficiency virus (HIV-1), and leptomeningeal disease in this setting has a dismal prognosis. We investigated the utility of brain CT in determining the outcome of leptomeningeal disease, despite MR imaging being the gold standard., Materials and Methods: From a cohort of 9621 HIV-1-seropositive individuals, we identified those diagnosed with ARL in the highly active antiretroviral therapy (HAART) era who had both a lumbar puncture and central nervous system imaging using a CT brain scan at the time of initial diagnosis, and we compared survival parameters between those with and without leptomeningeal disease., Results: In a cohort of 82 individuals with ARL treated in the era of HAART, we found that the survival of individuals with leptomeningeal disease defined as the presence of cells in the CSF was worse compared with that of other patients (P = .0026). However, when defined by the presence of abnormal enhancement or parenchymal lesions on a CT scan, the outcome was not significantly different., Conclusion: A CT brain scan appears not to offer additional prognostic information following a lumbar puncture in patients with ARL.

Introduction: Epstein-Barr virus (EBV) is detected in the cerebrospinal fluid (CSF) in people with HIV infection who develop primary cerebral lymphoma (PCL). However, EBV may also be detected in the CSF of patients without PCL, and here the significance is uncertain., Methods: Ninety-eight HIV-positive patients had lumbar punctures performed and polymerase chain reaction (PCR) for EBV was undertaken on the CSF. Thirty-eight patients had non-Hodgkin's lymphoma (NHL), including four with PCL. Sixty patients had a CSF examination for other indications. The clinicopathological details, symptoms, diagnosis, CSF and neuroimaging findings and therapy at time of CSF were recorded and correlated with CSF EBV PCR results., Results: EBV was detected in the CSF in three of four patients (75%) with PCL, one of three (33%) with systemic lymphoma and meningeal involvement, and four of 31 (13%) with systemic lymphoma and no meningeal disease. Seven of 60 patients (12%) without lymphoma were CSF EBV-positive. There were no differences in immunological, clinical, biochemical or radiological parameters between patients with and without EBV in the CSF. After a median follow-up time of 30 weeks (maximum 102 weeks), none of the seven CSF EBV-positive patients has developed PCL., Conclusion: EBV was detected in up to 12% of patients with neurological symptoms but without lymphoma. A positive result did not correlate with more advanced immunosuppression or a particular neurological diagnosis. Patients with EBV in their CSF did not appear to be at increased risk of developing PCL in the short term.

Highly active antiretroviral therapy (HAART) has had a dramatic effect on the natural history of HIV disease, reducing the incidence of opportunistic infections and Kaposi's sarcoma, and improving overall survival. Since HAART became available in 1996, the incidence of AIDS-related non-Hodgkin's lymphoma (NHL) has fallen, and although there has been no change in the clinical features at presentation, the overall survival of patients with AIDS-related NHL has improved. Prognosis is now determined chiefly by lymphoma-associated factors similar to those in the general population (the International Prognostic Index), although serum CD4 count at lymphoma diagnosis is an additional independent prognostic factor. The management of patients with AIDS-related NHL with either infusional chemotherapy or CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine and prednisolone) achieves response and survival rates approaching those observed in the general population. However, careful attention should be paid to central nervous system chemoprophylaxis, opportunistic infection prophylaxis and potential drug interactions between cytotoxic and antiretroviral therapies. In the era of HAART, the goal of therapy for these patients is now complete remission rather than palliation.

From a cohort of 9621 human immunodeficiency virus type 1-infected individuals, we identified 61 patients with primary central nervous system lymphoma (PCL) who had a median survival of 1.3 months. We compared clinicopathologic variables of patients who were treated in the pre-highly active antiretroviral therapy (HAART) and HAART eras and investigated whether exposure to antiretroviral agents with differing cerebrospinal fluid penetrations was associated with risk for PCL. All statistical tests were two-sided. Incidence of PCL was lower in the HAART era (1.2 cases per 1000 patient-years, 95% confidence interval [CI] = 0.8 to 1.9) than in the pre-HAART era (three cases per 1000 years, 95% CI = 2.1 to 4.0; P<.001), and overall survival was longer (median survival = 32 days, range = 5-315 days, versus 48 days, range = 15-1136 days; log rank P = .03). In the HAART era, fewer patients had prior acquired immunodeficiency syndrome-defining illnesses than in the pre-HAART era (64% versus 90%; P = .013), and patients were more likely to have the diagnosis of PCL confirmed histologically or by polymerase chain reaction (77% versus 26%; P<.001). Exposure to specific antiretroviral agents was not associated with risk for PCL.

Background: The established International Prognostic Index for lymphomas has not included patients with systemic AIDS-related non-Hodgkin lymphoma., Objective: To establish the most appropriate prognostic index for use in patients with systemic AIDS-related non-Hodgkin lymphoma., Design: A prospective study involving univariate and multivariable analyses of patients with AIDS-related non-Hodgkin lymphoma whose data were used to examine standard and new criteria for survival after diagnosis., Setting: The Chelsea and Westminster cohort of HIV-1-infected persons., Patients: 9621 HIV-positive patients, 111 in whom AIDS-related non-Hodgkin lymphoma was treated after 1996, in the era of highly active antiretroviral therapy (HAART)., Intervention: Cox proportional hazards regression analysis to determine the prognostic significance of multiple clinicopathologic variables., Results: Survival of patients with AIDS-related non-Hodgkin lymphoma has increased in the HAART era (log-rank chi-square, 9.23; P = 0.002). Univariate analyses using the established International Prognostic Index factors of age, tumor stage, lactate dehydrogenase level, Eastern Cooperative Oncology Group performance status, and number of extranodal sites were confirmed to be significant variables. Regression modeling for patients in whom disease was diagnosed after 1996 revealed only 2 independent predictors of death: International Prognostic Index risk group and CD4 cell count. These predictors yielded 4 internally validated risk strata with predicted 1-year survival rates of 82%, 47%, 20%, and 15% (P < 0.001). Prognostic risk scores in the highest quartile yielded a likelihood ratio for death of 7.90 (hazard ratio, 1.0), whereas a prognostic score less than 1.0 yielded a likelihood ratio of 0.23 (hazard ratio, 0.15 [95% CI, 0.06 to 0.33])., Limitations: The sample was small, and different HAART regimens were used., Conclusions: For patients with AIDS-related non-Hodgkin lymphoma that was diagnosed in the era of HAART, application of the International Prognostic Index remains useful. The addition of CD4 cell count provides further independent prognostic information. Patients who present with AIDS-related non-Hodgkin lymphoma and a low CD4 cell count have a poor prognosis; this information can be used to guide therapeutic options.

Immunosuppression induced by the human immunodeficiency virus (HIV) increases the risk of developing non-Hodgkin's lymphoma (NHL). As the hepatitis C virus (HCV) has been implicated in the development of B cell lymphomas, we compared the incidence of systemic NHL during HIV infection compared to HIV and HCV co-infection. Of 5,832 individuals studied during the era of highly active anti-retroviral therapy (HAART), 102 patients were diagnosed with systemic NHL. The incidence of systemic NHL was 6.9 of 10(4) patient years during HIV infection compared to 7.1 of 10(4) patient years during HIV alone (p = 0.9). In this immunocompromised patient population, there was no association between HCV infection and an increased risk of lymphoma., ((c) 2005 Wiley-Liss, Inc.)

We describe an audit of lymphoma care in HIV-positive patients. In the smaller units (< 500 patients) areas of potentially sub-optimal care were identified.

Pharmacokinetic interactions between chemotherapy and highly active antiretroviral therapy (HAART) are described, but there are few data on their clinical relevance. Patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) were treated with concomitant HAART and infusional cyclophosphamide-doxorubicin-etoposide (CDE) chemotherapy. We compared neutropenia according to whether patients received protease inhibitor (PI)-based HAART or non-PI regimens. Differences in survival, response rates, immunologic parameters, and virologic parameters were also investigated. The day-10 (Mann-Whitney U test; P = .012) and day-14 (P = .025) neutrophil counts were significantly lower in patients receiving PIs, though there were no differences in the number of days of granulocyte colony-stimulating factor (G-CSF) administered between groups (P = .16). Grade 3 or 4 infections requiring hospitalization were recorded for a total of 58 (31%) of 190 cycles of CDE: 23 (48%) of 48 when prescribed PIs and 35 (25%) of 142 with concomitant PI-sparing HAART (chi(2) test; P = .0025). There were no statistically significant differences in the response rates, relapse-free survival, or disease-free survival between patients receiving PIs and those not receiving PIs. PI-based HAART appears to significantly potentiate the myelotoxicity of CDE chemotherapy. This potentiation may be a consequence of microsomal enzyme inhibition reducing the metabolism of cytotoxics in this regimen.

Purpose: Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens., Patients and Methods: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (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 entered in univariate and multivariate analyses to establish and stratify the risk of NHL., Results: From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, 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 <.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 <.02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as 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 antiretrovirals (P <.001)., Conclusion: Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.

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.

The treatment and outcome of human immunodeficiency virus (HIV) infection altered dramatically in the mid-1990s with the introduction of highly active antiretroviral therapy (HAART). Highly active antiretroviral therapy, where available, has led to a dramatic decline in mortality from HIV and a decrease in the incidence of opportunistic infections and Kaposi sarcoma. This article addresses the effects that HAART has had on acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL). Metaanalysis of numerous cohort studies confirmed that the incidence of AIDS-related NHL has decreased since the advent of HAART. This decline is most marked for primary cerebral lymphomas and systemic immunoblastic lymphoma but has not been demonstrated for Burkitt lymphoma. In addition to genetic predisposing factors, age, nadir CD4 cell count, and lack of HAART therapy predict the development of NHL. The clinical presentation of AIDS-related NHL has not changed, but several institutions have reported an improvement in survival since the introduction of HAART. Moreover, HAART has been combined safely with systemic chemotherapy in the management of NHL, and this approach results in a more modest decrease in immune function than when chemotherapy is administered alone. This has led to a more aggressive approach to the management of AIDS-related NHL and response rates and overall survival durations that are approaching those seen in stage-matched high-grade lymphomas in the immunocompetent population.

People with HIV infection who commence highly active antiretroviral therapy (HAART) occasionally develop reactivation of subclinical infection. This clinical entity is termed immune reconstitution inflammatory syndrome (IRIS) and is defined as a paradoxical deterioration in clinical status as a result of recovery of the immune system during HAART. We present three cases of IRIS following a diagnosis of AIDS related non-Hodgkin's lymphoma that resembled lymphoma relapse.

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 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., 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.

Objective: To measure the effects of combined chemotherapy and highly active antiretroviral therapy (HAART) on immune cell counts and plasma HIV-1 RNA loads in patients with AIDS-related lymphoma (ARL) to determine the implications for opportunistic infection prophylaxis and medium-term immune function., Design and Methods: Peripheral blood total lymphocyte count, CD4 T-cell count, CD8 T-cell count, CD19 B-cell count, CD16/CD56 natural killer cell count and plasma HIV-1 RNA load were prospectively measured at ARL diagnosis, at 1 and 3 months during and 1, 3 and 6 months after chemotherapy in twenty patients receiving HAART., Results: Significant declines in T-helper cell (CD4) count, natural killer cell (CD16/CD56) and B lymphocyte count (CD19 cells) occurred during the first 3 months of chemotherapy. There was no significant alteration in the T-cytotoxic cell (CD8) count, CD4 percentage or HIV-1 RNA load during the study period. The T-helper cell and natural killer cell counts recovered to pre-treatment levels within 1 month of finishing chemotherapy. The recovery of B-cells was slower with pre-treatment levels only being achieved after 3 months. The recovery of CD4 T-cell count following completion of chemotherapy was more rapid than described for ARL patients who were not receiving concomitant HAART., Conclusions: By combining chemotherapy with HAART, immune function is better maintained in the medium term. The CD4 T-cell count falls by 50% during chemotherapy and this will help to identify patients who require opportunistic infection prophylaxis during chemotherapy.

Three important issues have been the focus of much recent attention in the biology of AIDS-related lymphomas. The altered epidemiology in the era of highly active antiretroviral therapy, the role of herpesviruses including human herpesvirus 8 and the molecular genetics of HIV-associated T-cell lymphomas. These topics are covered in this article and their potential application to the clinical management of AIDS-related lymphomas are discussed.

Clinical data on 7840 HIV-positive patients, representing 43 745 patient-years of follow-up, has been collected. All patients with ARL since 1986 (n = 150) were assessed at presentation for prognostic factors and outcomes recorded. Comparisons are made between cases in the pre-HAART era (1988-1995), and the HAART era (1996-1999). Statistical models are used to calculate the incidence of ARL and factors predicting its development. The incidence of ARL has not changed over time (3 to 7 of 1000 patients per year, P = .933), but contributes to a greater percentage of first AIDS-defining illnesses (ADI) in the HAART era (P < or = .0001). Older age, nadir CD4 count, and no prior HAART use, predict the development of ARL. There has been no change in stage at presentation, presence of B symptoms, performance status, or marrow involvement between the 2 time cohorts or between patients with or without prior HAART exposure. Similarly, there is no difference in survival duration between the pre-HAART and HAART era (log rank P = .15) or specifically in patients treated with HAART before ARL diagnosis (log rank P = .12). The use of HAART has not yet been shown to influence the incidence or survival of ARL. However, because nadir CD4 count and use of HAART are independent predictors of ARL development, this may translate into a future fall in new cases. (Blood. 2000;96:2730-2734)

Objective: To review the current literature on HIV associated non-Hodgkin's lymphoma., Methods: A comprehensive Medline/Pubmed search of articles pertaining to HIV associated non-Hodgkin's lymphoma as well as personal experience from the treatment of over 200 patients at the Chelsea and Westminster Hospital, one of the largest centres for the management of HIV disease in Europe., Conclusion: High grade B cell non-Hogdkin's lymphoma is the second commonest tumour affecting people with HIV. The incidence of this tumour is not declining following the introduction of highly active antiretroviral therapy. Chemotherapy has been employed with modest success in this group of patients; however, the prognosis remains worse than for immunocompetent patients. Advances in molecular genetics and virology have led to a greater understanding of the biology of these tumours. However, these advances have yet to be translated into improvements in the clinical management of patients with AIDS associated non-Hodgkin's lymphoma.

Early studies reported that the major adverse prognostic factors in AIDS-related non-Hodgkin's lymphoma (ARL) are low CD4 cell count, prior AIDS defining diagnosis and poor performance status. Since 1989 we have adopted a prognosis-stratified approach for ARL. In this study, we identified a group of good prognosis patients. These patients with one or no adverse prognostic factors were treated with alternating weekly chemotherapy using the bleomycin, etoposide, vincristine, methotrexate, prednisolone/cyclophosphamide, doxorubicin (BEMOP/CA) schedule (Bower M, Block C, Gulliford T, et al. Cancer Chemother Pharmacol 1995, 38, 106-109). Modifications to the regimen with the aim of reducing toxicity were a briefer duration (12 weeks) and the addition of prophylaxis against pneumocystis and mycobacteria. Intrathecal methotrexate was administrated fortnightly to patients with Burkitt's histology, meningeal involvement or base of skull disease. 30 patients were treated, including 5 with prior AIDS, 3 with ECOG status 3 and 1 with CD4 <100/microl. The mean age was 40 (range 22-60 years), the median CD4 cell count at ARL diagnosis was 262/microl (range 44-588/microl). The International non-Hodgkin's lymphoma (NHL) prognostic factors project classifications were low risk 8 (maximum 5.4 years) (27%), low-intermediate risk 6 (20%), high-intermediate risk 11 (37%) and high risk 5 (17%). The median follow-up was 2.1 years. 3 patients withdrew from treatment within 2 weeks due to toxicity, 2 patients died within 2 weeks of starting chemotherapy. The major toxicity was myelosuppression with 14 patients developing grade 4 neutropenia. The 2-year overall survival rate is 46% (95% confidence interval (CI)=27-65%), and lymphoma-specific survival at 2 years is 59% (95% CI: 40-78%). For selected patients with good prognosis ARL 12 weeks BEMOP/CA therapy produces good overall survival at 2 years.

A retrospective analysis identified 38 HIV seropositive patients with a diagnosis of presumed (n = 26) or confirmed (n = 12) primary cerebral lymphoma (PCNSL). All patients had failed to respond to empirical antitoxoplasma therapy and the clinical diagnosis of PCNSL was confirmed by brain biopsy (n = 4), cerebrospinal fluid (CSF) examination for Epstein-Barr virus (EBV) by PCR (n = 7) or postmortem examination (n = 1). There was no difference in the age, performance status, CD4 counts, antiretroviral usage or interval since first HIV serodiagnosis between patients with presumed or confirmed PCNSL. 16 patients received either radiotherapy (n = 14) or chemotherapy (n = 2). Patients with confirmed or presumptive PCNSL were equally likely to receive treatment. The median overall survival, which was measured from the end of unsuccessful antitoxoplasma therapy, was 1.2 months for the whole cohort. There was no difference in overall survival between patients with presumptive (median 0.8 months) and confirmed (median 1.3 months) PCNSL (logrank P = 0.69). This suggests that there may be little value in positively diagnosing PCNSL in the current diagnostic algorithm. Recent improvements in outcome have been reported with systemic chemotherapy in HIV-PCNSL and may influence the need for earlier definitive diagnosis in the future.