[Diagnosis, prophylaxis and treatment of central nervous system involvement by non-Hodgkin lymphoma in HIV-infected patients]. / Diagnóstico, profilaxis y tratamiento de la afectación del sistema nervioso central por linfoma no hodgkiniano en pacientes con infección por el virus de la inmunodeficiencia humana.

With the widespread use of highly active antiretroviral therapy (HAART) the incidence of systemic non-Hodgkin lymphoma (NHL) in patients infected with the Human Immunodeficiency Virus (HIV) has declined. HAART has also modified the clinical manifestations of these tumors, with a lower frequency of involvement of the central nervous system (CNS). Currently, the frequency of meningeal involvement at the time of diagnosis of NHL in HIV-infected patients varies between 3% and 5%. These figures are similar to those observed among immunocompetent hosts. The diagnosis of meningeal lymphoma relies in clinical findings, imaging techniques, and cerebrospinal fluid (CSF) examination. Flow cytometry is a diagnostic technique with a higher sensitivity and specificity than conventional cytology for the diagnosis of meningeal lymphoma. However, flow cytometry is not yet considered to be the gold standard for this purpose. Until recently, most experts recommended neuromeningeal prophylaxis for all HIV-infected patients with aggressive NHL. However, at present this prophylaxis is recommended only in patients with higher risk of CNS relapse according to different sites of involvement, stage and histological subtype. There are different regimens of prophylaxis and treatment for meningeal lymphoma. The drugs most commonly used for this purpose are methotrexate and cytosine arabinoside. However, there are other alternatives such as liposomal cytosine arabinoside that requires fewer spinal taps for drug administration and whose results are very promising. In summary, in the context of an effective HAART, HIV infected patients with NHL have a frequency of CNS involvement by lymphoma similar to that found among immunocompetent hosts. Consequently, indications and regimens for CNS prophylaxis in HIV-infected patients with NHL should not be different than those employed in the general population. Universal CNS prophylaxis should be reserved for the few patients unable to receive an effective HAART.

Immunotherapy for HIV-associated non-Hodgkin's lymphoma.

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.

Decrease in the frequency of meningeal involvement in AIDS-related systemic lymphoma in patients receiving HAART.

We evaluated the frequency of primary central nervous system lymphoma and leptomeningeal involvement in systemic non-Hodgkin's lymphoma (NHL) in HIV-infected patients. Those receiving highly active antiretroviral therapy (HAART) showed a decrease in leptomeningeal involvement in systemic NHL (0/30 vs. 12/87; p=0.023). Therefore HAART could prevent CNS involvement in systemic NHL.

Highly active antiretroviral therapy and human immunodeficiency virus-associated primary cerebral lymphoma.

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.

Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma.

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.

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 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.

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.

Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy.

HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P < 10(-30)). The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10 000 to 9.7 per 10 000 person-years (P < 10(-11)). The analysis of 145 cases of ARL in 3 hospitals showed that known HIV history was longer in the second period than in the first period among patients with systemic ARL (98 versus 75 months; P <.01). Patients had a higher number of CD4 cells at diagnosis during the second period (191 versus 63/microL, P = 10(-3)). Survival of patients with systemic ARL also increased between the periods (from 6 to 20 months; P =.004). Therefore, the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved.

Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults.

BACKGROUND: The risk of Kaposi's sarcoma and non-Hodgkin's lymphoma is increased in people infected with the human immunodeficiency virus-1 (HIV). Highly active antiretroviral therapy (HAART) has been widely used by HIV-infected people in North America, Europe, and Australia since about 1997. Acquired immunodeficiency syndrome (AIDS) incidence and mortality rates have fallen markedly in association with the use of HAART, but its impact on the incidence of cancer in HIV-infected people is less clear. METHODS: Cancer incidence data from 23 prospective studies that included 47 936 HIV-seropositive individuals from North America, Europe, and Australia were collated, checked, and analyzed centrally. Adjusted incidence rates (expressed as number of cancers per 1000 person-years) for Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, cervical cancer, and 20 other cancer types or sites were calculated. Rate ratios were estimated, comparing incidence rates from 1997 through 1999 with rates from 1992 through 1996, after adjustment for study, age, sex, and HIV transmission group. All statistical tests were two-sided. RESULTS: For the period from 1992 through 1999, 2702 incident cancers were reported in 138 148 person-years of observation, and more than 90% of them were either Kaposi's sarcoma or non-Hodgkin's lymphoma. The adjusted incidence rate for Kaposi's sarcoma declined from 15.2 in 1992 through 1996 to 4.9 in 1997 through 1999 (rate ratio = 0.32; 99% confidence interval [CI] = 0.26-0.40; based on 1489 and 190 cases, respectively; P<.0001). The incidence rates for non-Hodgkin's lymphoma also declined, from 6.2 to 3.6 (rate ratio = 0.58; 99% CI = 0.45-0.74; based on 623 and 134 cases, respectively; P<.0001). Among the lymphomas, the rate ratios were 0.42 (99% CI = 0.24-0.75) for cerebral lymphoma, 0.57 (99% CI = 0.39-0.85) for immunoblastic lymphoma, and 1.18 (99% CI = 0.48-2.88) for Burkitt's lymphoma (chi(2)(2) for heterogeneity = 6.2; P: =.05). There was no statistically significant change in the incidence rates for Hodgkin's disease (rate ratio = 0.77; 99% CI = 0.32-1.85; based on 38 and 12 cases, respectively; P =.4) or for cervical cancer (rate ratio = 1.87; 99% CI = 0.77-4.56; based on 19 and 17 cases, respectively; P =.07). The adjusted incidence rate for all other cancers combined was 1.7 in each time period (rate ratio = 0.96; 99% CI = 0.62-1.47; based on 126 and 54 cases, respectively). CONCLUSIONS: Since the widespread use of HAART, there have been substantial reductions in the incidence Kaposi's sarcoma and non-Hodgkin's lymphoma in HIV-infected people but, so far, no substantial change in the incidence of other cancers.

Value of long-term administration of acyclovir and similar agents for protecting against AIDS-related lymphoma: case-control and historical cohort studies.

Acyclovir or similar agents with activity against Epstein-Barr virus (EBV) theoretically may prevent non-Hodgkin's lymphoma (NHL) in AIDS. A case-control study of 29 patients with AIDS-related NHL and 58 matched control subjects assessed the frequency with which daily acyclovir (>/=800 mg/d) or similar agents were used for > or =1 year. In a historical cohort of 304 patients with AIDS for > or =2 years, the prevalence of NHL was assessed among 3 groups of patients: those who received long-term treatment with high-dose acyclovir (or similar agents) or low-dose or intermittent acyclovir; those treated with ganciclovir/foscarnet for <1 year; and those who had not previously been treated with acyclovir, ganciclovir, or foscarnet. In the case-control study, 22 patients (72.4%) with NHL never received acyclovir or similar drugs versus 19 control subjects (32.8%; P=. 002); 2 patients (6.9%) with NHL received acyclovir (> or =800 mg/d) for > or =1 year versus 27 (46.6%) of control subjects (P=.0001). In the cohort study, 6 (6.8%) of 88 patients who received acyclovir (> or =800 mg/d) for > or =1 year developed NHL versus 15 (15.5%) of 97 patients who received intermittent or lower-dose acyclovir and 30 (25.2%) of 119 patients who never received these agents (P=.002). Long-term administration (>1 year) of high-dose acyclovir or similar agents with anti-EBV activity may prevent NHL in patients with AIDS. A prospective, randomized study is warranted to confirm these results.

Ancillary benefits of Mycobacterium avium-intracellulare complex prophylaxis with clarithromycin in HIV-infected patients.

Because of the significant morbidity and mortality associated with opportunistic infections, prophylaxis has become routine practice in the management of immunocompromised patients such as those with AIDS. Clarithromycin, an antimicrobial agent with a broad spectrum of activity against most common respiratory pathogens as well as many protozoa, has proven to be effective for both treatment and prophylaxis of Mycobacterium avium-intracellulare complex (MAC) infection in AIDS patients. Results of a large multinational placebo-controlled study suggest that clarithromycin for MAC prophylaxis provides additional benefits. In this study, clarithromycin statistically significantly reduced the incidence of Pneumocystis carinii pneumonia (5.3% of clarithromycin recipients vs 10.0% of placebo recipients; p = 0.021), community-acquired pneumonia (7.1 vs 13.0%; p = 0.010), Giardia lamblia infection (0.9 vs 2.9%; p = 0.048), and neoplastic diseases (1.8 vs 4.1%; p = 0.010) in AIDS patients with CD4+ counts of < or = 100 cells/microliter.

The pathogenesis of AIDS lymphomas: a foundation for addressing the challenges of therapy and prevention.

The association between AIDS and a spectrum of malignancies relates to chronic, profound defects in both cellular and humoral mechanisms of immune surveillance. Ironically, as AIDS patients live longer in response to increasingly effective antiretroviral therapies, the incidence of AIDS-related malignancies will continue to rise. The emergence of non-Hodgkin's lymphomas (NHL) as a major sequela of HIV infection bears a striking relationship to depletion of CD4 lymphocytes, particularly below 50/mm3. The ability to interfere early in the course of active HIV infection with additional mechanisms that may promulgate transformed cell hyperproliferation and clonal expansion--growth factors, HIV itself or other viruses (Epstein-Barr, in particular), aberrant oncogene or tumor suppressor genes expression, factors that induce genetic instability or DNA damage or alter host or viral genome repair--might decrease the occurrence or prolong the time to development of AIDS-related malignancies. The development of antiretroviral strategies that confer long-term suppression of HIV activity and relative preservation of immune function are essential to the ultimate prevention of malignancies that arise as a consequence of HIV-induced immunosuppression.