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PURPOSE OF REVIEW: Human immunodeficiency virus infection is associated with an increased risk of non-Hodgkin lymphoma. Even with a decrease in AIDS-defining illnesses after the advent of highly active antiretroviral therapy, HIV-associated non-Hodgkin lymphoma remains an important problem. RECENT FINDINGS: Low CD4+ T-lymphocyte count, disease stage, performance status, serum lactate dehydrogenase, and number of extranodal sites of disease are all important prognostic factors for HIV-non-Hodgkin lymphoma. Recent studies have examined the role of infusional chemotherapy, as well as immunotherapy, in the treatment of aggressive HIV-non-Hodgkin lymphoma, and autologous stem cell transplantation for relapsed or refractory HIV-non-Hodgkin lymphoma. New developments in the association of viral infection and pathogenesis of certain subtypes of HIV-non-Hodgkin lymphoma have also recently been reported. SUMMARY: Outcomes of HIV-non-Hodgkin lymphoma are improving with the routine use of highly active antiretroviral therapy and combination chemotherapy. For aggressive HIV-non-Hodgkin lymphoma, infusional chemotherapy regimens are well tolerated and lead to complete response in about 50-75% of cases and a 2-3 years overall survival of 40-60%. The potential benefit of adding rituximab to combination chemotherapy may be offset by infectious complications in severely immunosuppressed patients. HIV-associated Burkitt lymphoma should be treated with an intensive regimen rather than standard cyclophosphamide, doxorubicin, vincristine, prednisone-like chemotherapy. Autologous stem cell transplantation should be considered for selected patients with relapsed or refractory HIV-non-Hodgkin lymphoma.

Objective To assess the efficacy, safety and tolerance of oral 9-cis-retinoic acid in HIV-infected patients with Kaposi's sarcoma. Methods Sixty-six patients with AIDS-related Kaposi's sarcoma were enrolled at 14 centers; 60 received the study medication and were analyzed and, of these, 45 (75%) had received prior therapy for Kaposi's sarcoma. Once daily oral 9-cis-retinoic acid (alitretinoin, Panretin) was administered at doses up to 140 mg/m 2 . Most patients (72%) received a maximum dose of 100 mg/m 2 . Response was assessed using AIDS Clinical Trials Group (ACTG) criteria. Results The median age was 38 years and the median absolute CD4 cell count was 194 × 10 6 cells/I (range 6-784 × 10 6 ). Despite the use of three- and four-drug antiviral regimens (83%), the median HIV RNA at baseline was 8701 copies/ml Irange < 500 (lower limit of detection) to 4.24 × 10 6 ]. The tumor response rate was 37% (95% confidence interval 25-49). Tumor response was associated with improved quality-of-life measures. There was a significant increase in interleukin 6 (IL-6) levels from baseline to week 4. Responders had significantly lower baseline soluble IL-6 receptor levels (P = 0.029) than non-responders. The median time to response was 9 weeks (mean, 13 weeks; range, 4-36). HIV RNA levels did not change significantly during therapy nor did they correlate with tumor responses. Study drug was discontinued by 28 patients for adverse events, which included headache (13) and skin toxicity (10). Conclusion Oral 9-cis-retinoic acid is an active antitumor drug for AIDS-related Kaposi's sarcoma. Treatment is associated with skin and constitutional toxicity and further studies are needed to improve its long-term tolerance.

The AIDS-associated lymphomas represent a heterogeneous set of disease processes. The largest histologic subset of lymphomas is the large-cell lymphomas, which represent a spectrum of disease processes ranging from monomorphic monoclonal B-cell proliferations to very polymorphic and polyclonal mixtures of B cells, T cells and macrophages. The next most frequent class of systemic lymphoma are the small non-cleaved cell or Burkitt's-like lymphomas. These are relatively monomorphic, monoclonal malignant B-cell proliferations. The final subset of lymphomas, which are likely to become more common as the AIDS epidemic progresses, are the primary CNS lymphomas, which are expansions of EBV-immortalized B cells. The high incidence of tumor-associated EBV in the CNS lymphomas makes these lesions somewhat analogous to an opportunistic EBV infection. In HIV disease there is a long lag after infection before the appearance of clinical manifestations of impaired T-cell immunity. During this period, both appropriate B-cell proliferation in response to antigen (including the ubiquitous HIV) and abnormal B-cell proliferation (autoimmune, dysregulated) occur as the follicular architecture is disrupted by the virus and potential APC are exposed and/or infected with HIV. The destruction of FDC or the involution of their processes could interfere with the elimination by apoptosis of low-avidity B-cell clones. Antigen-competent B cells with pre-existing chromosomal translocations such as the t(8;14) (c-myc, IgH) would have a selective growth advantage in this setting. Figure 9 shows a schematic representation of prelymphomatous and lymphomagenic events as they are projected to occur. A similar pathogenetic scheme has been postulated for follicular B-cell lymphomas: PCR studies have demonstrated that a pool of t(14;18) (IgH;bcl-2) B-cells are present in lymph nodes featuring follicular hyperplasia. In response to antigen (the evidence favoring antigen drive is extensive hypersomatic mutation in sequences related to binding sites), B cells with the t(14;18) translocation have a selective advantage because the bcl-2 oncogene confers a resistance to apoptosis. Burkitt's lymphomas, particularly sporadic or HIV variants, fulfill at least the key criteria for antigen competence, mainly the presence of surface Ig. The c-myc-associated chromosomal translocational events are likely to occur early during the enzymatic machinations of gene rearrangement. Such B cells would be in the dysregulated cytokine and antigen milieu of HIV disease and ultimately could have a selective advantage. EBV infection of B cells probably requires activation and expression of the CD21 receptor. Furthermore, CD5+ B cells of CLL are refractory to EBV infection.(ABSTRACT TRUNCATED AT 400 WORDS)

The number of cases HIV-associated non-Hodgkin's lymphoma continues to increase as the AIDS epidemic grows. Approximately 3% of AIDS-defining illnesses are non-Hodgkin's lymphoma. The number of non-Hodgkin's lymphoma cases may actually be higher because many cases go unreported. There is also evidence that increasing numbers of patients who are surviving longer on antiretroviral therapy are developing non-Hodgkin's lymphoma. A majority of HIV-related lymphomas are large cell, either high-grade immunoblastic or aggressive intermediate grade, diffuse cleaved, or small noncleaved (Burkitt's-like). HIV-related non-Hodgkin's lymphomas behave aggressively. They are predominantly extranodal and often show unusual patterns of organ involvement. They are typically stage III or IV at the time of diagnosis. Current treatment strategies involve the use of combination chemotherapy regimens with or without antiretroviral therapy. Current studies are evaluating the efficacy of low-dose chemotherapy regimens versus standard-dose regimens with granulocyte-macrophage colony-stimulating factor support. New strategies for treating AIDS-associated non-Hodgkin's lymphoma will incorporate our current knowledge of AIDS-related lymphoma pathogenesis. Factors that reflect a patient's state of immunodeficiency seem to be the most important prognostic features determining clinical outcome after treatment. Patients with good prognostic features may benefit the most from aggressive treatment regimens. AIDS-related primary central nervous system lymphomas continue to comprise approximately 15% of AIDS-related non-Hodgkin's lymphoma cases. Treatment is limited. Although whole-brain radiation therapy can result in an improved neurologic status, the median survival remains 3 to 4 months.(ABSTRACT TRUNCATED AT 250 WORDS)

The association of malignant lymphoma with the acquired immunodeficiency syndrome (AIDS) has been recognized since early in the human immunodeficiency virus epidemic. Important clues regarding the etiology of AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) and estimates of the future incidence of AIDS-NHL have been derived from epidemiologic studies. Recent epidemiologic and cohort studies reviewed in this article have confirmed that the incidence of non-Hodgkin's lymphoma is high in patients with human immunodeficiency virus infection, and increase with the duration of severe immunodeficiency in patients receiving antiretroviral therapies. A recent retrospective analysis of clinical features associated with AIDS-NHL described two groups of patients possessing distinct prognostic features. Finally, a number of new observations relating to the molecular and pathogenic mechanism underlying the development of AIDS-NHL have recently been described. The role of Epstein-Barr virus in the pathogenesis of AIDS-NHL continues to be enigmatic, and there may be multiple mechanisms contributing to the development of lymphoma, even in an individual patient.

A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

Our objective was to examine the efficacy and toxicity of continuous, low-dose interferon-alpha therapy for human immunodeficiency virus-related immune thrombocytopenic purpura (HIV-ITP) in a Phase II clinical trial overseen by a community-based consortium of physicians conducting clinical trials in HIV-related diseases. Sixteen patients with HIV-ITP defined by prospective clinical criteria were enrolled; the majority had failed other therapies for HIV-ITP. Baseline and serial measurements were made of platelet counts, complete blood counts, serum chemistries, platelet-associated immunoglobulin, and CD4+ T-lymphocyte counts; subjective symptoms and bleeding were recorded. Three million units of interferon-alpha 2b were self-administered by subcutaneous injection every Monday, Wednesday, and Friday for 16 weeks. Thirteen participants were evaluable for response. One obtained a complete response, eight had partial responses, and four had no response to interferon-alpha therapy. The mean absolute platelet count of the group rose from 15.5 x 10(9)/L at baseline to 47.3 x 10(9)/L at 2 weeks and remained in this range for the duration of the study. CD4+ T-lymphocyte counts and serum chemistries did not change significantly during therapy. Ability to detect platelet-associated immunoglobulin did not change in a predictable manner in relation to platelet count response. Hematologic toxicity was limited to one episode of granulocytopenia, which resolved after a lowering of zidovudine dosage. Subjective toxicities were mild and tolerable, and minor bleeding problems improved in all participants so affected. Low-dose, continuous therapy with interferon-alpha resulted in meaningful increases in the platelet counts of the majority of study participants with HIV-ITP. Interferon-alpha was safe and tolerable for most participants with HIV-ITP at the dosage and schedule employed in this study. Interferon-alpha for clinically significant thrombocytopenia and who have failed to respond to zidovudine.

To assess the response and toxicity of liquid nitrogen cryotherapy for cutaneous lesions of Kaposi's sarcoma (KS) associated with AIDS, we evaluated 20 subjects with biopsy-proven KS in a phase II clinical trial. Subjects had two to four cutaneous KS indicator lesions treated with liquid nitrogen cyrotherapy. Treatment was repeated at 3 week intervals, allowing adequate healing time. On average, subjects received three treatments per lesion with a mean follow-up time of 11 weeks (range of 6-25 weeks). One treatment consisted of two freeze-thaw cycles, with thaw times ranging from 11 to 60 s per cycle. A complete response was observed in 80% of treated KS lesions and lasted a minimum of 6 weeks following the completion of therapy. Greater than 50% cosmetic improvement of KS was observed. Histopathology of treated lesions correlated poorly with cosmetic improvement. Response was not predicted by tolerance to zidovudine therapy, CD4+ cell count, presence of B symptoms, or previous chemotherapy. Subjects without prior history of opportunistic infection (OI) were more likely to have a better response than those with a prior history of OI. Subjects tolerated cryotherapy well. Blistering occurred frequently, but local pain was limited and relieved by acetaminophen. Secondary infection did not occur. Based on this study, we recommend cryotherapy to subjects with cutaneous KS lesions. Liquid nitrogen cryotherapy is easily applied as a primary therapy, and may also have a role in the treatment of cutaneous KS lesions that respond slowly or show incomplete cosmetic improvement with systemic therapies.