Date Published: March 26, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Matthew Ulrickson, Oliver W. Press, Corey Casper.
Lymphoma was a common complication of HIV infection in the pre-antiretroviral era, and the incidence of HIV-associated lymphoma has dropped dramatically since the introduction of combination antiretroviral therapy (cART) in resource-rich regions. Conversely, lymphoma is an increasingly common complication of HIV infection in resource-limited settings where the prevalence of HIV infection is high. Relatively little is known, however, about the true incidence and optimal treatment regimens for HIV-associated lymphoma in resource-poor regions. We review the epidemiology, diagnosis, and treatment of HIV-associated non-Hodgkin lymphoma in developing nations and highlight areas for further research that may benefit care in both settings. Examples include risk modification and dose modification of chemotherapy based on HIV risk factors, improving our understanding of the current burden of disease through national cancer registries, and developing cost-effective hematopathological diagnostic strategies to optimize care delivery and maximize use of available chemotherapy.
An association between the acquired immunodeficiency syndrome (AIDS) and lymphoma was first suggested in 1982 after four young men in San Francisco with severe immunodeficiency were diagnosed with a “Burkitt-like lymphoma” [1, 2]. Since that time, HIV has been identified as the causative agent of the underlying immunodeficiency and non-Hodgkin lymphoma (NHL) was designated as an AIDS-defining malignancy . While most of the early descriptions of the emerging immunodeficiency syndrome were reported in patients living in the United States, most of the burden of HIV disease now affects resource-limited nations, with approximately two-thirds of HIV-positive individuals living in sub-Saharan Africa and only 8% within Western nations . The discovery and widespread use of combination antiretroviral therapy (cART) in resource-rich countries has both decreased the incidence of HIV-associated lymphoma and improved its prognosis [5, 6]. While the availability of cART has improved in resource-poor nations due to extraordinary recent efforts, similar changes in the incidence and outcome of HIV-associated lymphomas have not yet been noted. Therefore, increased efforts should be dedicated to improving the diagnosis, supportive care, and treatment of this disorder in these nations.
The incidence of the three AIDS-defining NHLs, diffuse large B-cell lymphoma (DLBCL), primary CNS lymphoma, and Burkitt lymphoma (BL), increased steadily in the United States between 1981 and 1990, at which time the incidence rate leveled off and began declining with the widespread availability of cART in 1996 . Over 25,000 Americans with HIV have been diagnosed with NHL since the beginning of the HIV pandemic .
A necessary complement to expanded cancer registry data in resource-poor nations is continued improvement in diagnostic accuracy, especially of hematological neoplasms. The accurate diagnosis of lymphomas can be challenging, even for pathologists in developed nations without hematopathological specialization. Diagnostic modifications were made in 20% of a series of submitted lymphoma cases in the United Kingdom after central review. After evaluation of associated clinical data in each of the cases, the authors concluded that clinical management likely would have differed in about half of the cases with diagnostic discrepancies . Similarly, the diagnosis of lymphoma in developing nations is challenging and significant modifications in final diagnosis have been reported after hematopathology review. A retrospective analysis of 207 NHL cases in Kenya resulted in the histologic reclassification of 41% of the cases . An additional study by Parkins and authors reviewed 150 cases of suspected lymphoproliferative disorders from two teaching hospitals in Ghana at the time of diagnosis. After this review, modifications were made to the diagnoses of 44% of patients, and alterations in the subsequent clinical management in 31% of the 150 patients as a result. Some of the final diagnoses in this group included nasopharyngeal carcinoma and tuberculosis, with marked differences in management resulting . The rates of significant diagnostic changes do vary between studies, however. In a prospective trial of combination chemotherapy in HIV-associated lymphoma in East Africa, pathological review led to changes in diagnosis in only 6% of the 32 patients with tissue samples available. Additionally, when the outcomes of patients with pathological confirmation were compared to those that did not undergo pathological review, no differences in outcome were noted .
At the present time, standard therapy for HIV-associated lymphoma in Africa does not include targeted therapy, such as rituximab, as current medication costs are prohibitive. Therefore, treatment is delivered with standard cytotoxic agents alone. Because of the similarities between the current patient population in resource-limited nations and patients in resource-rich nations in the pre-cART era, a historical review of chemotherapy for HIV-associated lymphomas is helpful for identifying potential areas of further study.
After the discovery and widespread use of cART in resource-rich countries, overall survival in HIV-associated lymphoma improved, in one study from an average of 6 months to 20 months , and more aggressive treatment regimens were once again considered. With the additional immunological support enabled with cART, the next major trial of chemotherapy in HIV-associated lymphoma compared CHOP to rituximab-CHOP combination therapy and was reported by Kaplan and authors as part of the AIDS Malignancy Consortium trial 010. This study found a trend towards increased efficacy (CR rate of 58% versus 47%) in the rituximab plus chemotherapy arm, however, also noted a significantly increased risk of treatment-related death in the combination arm of 14% compared to 2%. This increased risk of death was attributed to increased infectious complications during the treatment course and, on additional analysis, seemed to predominate in patients with CD4 counts <50 cells/μL. This finding supports the importance of risk stratification by CD4 count, even in patients on cART at the start of chemotherapy . Since platelet transfusions are currently not routinely available in most resource-limited nations , conditions exist to study chemotherapy regimens that decrease the need for transfusion and to evaluate adjunctive therapies that may decrease bleeding complications in the setting of thrombocytopenia such as aminocaproic acid . This could improve our understanding of the optimal management of patients in resource-rich nations that have an objection to receiving blood products. While a large portion of the improvements in treatment of HIV-associated lymphomas in resource-limited nations will occur as a result of earlier diagnosis, increased access to cART, and optimal treatment of concurrent infectious disease, significant opportunities to improve the hematological management of such cases also exist. Some of these advances may also benefit patients with HIV-associated lymphoma in resource-rich nations. Examples include improved risk modification and dose modification of chemotherapy, improved diagnostic capabilities with eventual implementation of targeted therapies based on the immunophenotypic profile, and an increased understanding of optimal supportive care for patients with infectious comorbidities. Source: http://doi.org/10.1155/2012/932658