© The Author 2006. Published by Oxford University Press.
BRIEF COMMUNICATION |
Highly Active Antiretroviral Therapy and Human Immunodeficiency Virus–Associated Primary Cerebral Lymphoma
Affiliations of authors: Departments of Oncology and HIV Medicine, The Chelsea and Westminster Hospital, London, United Kingdom
Correspondence to: Justin Stebbing, MA, MRCP, PhD, Department of Oncology, The Chelsea and Westminster Hospital, 369 Fulham Rd., London SW10 9NH, UK (e-mail: justinstebbing{at}gmail.com).
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ABSTRACT |
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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.
In persons with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and for whom it is available, highly active antiretroviral therapy (HAART) has decreased the morbidity and mortality associated with HIV, mainly by reducing the incidence of opportunistic infections, such as Pneumocystis carinii pneumonia (1,2). HAART, consisting of at least three antiretroviral drugs in accordance with published guidelines (3,4), has also been shown to result in a decreased incidence of common HIV-associated cancers (5–7), including an increased time to disease progression (8,9).
Primary central nervous system lymphoma (PCL) is defined as non-Hodgkin lymphoma (NHL) that is confined to the craniospinal axis without systemic involvement. It is uncommon in immunocompetent patients but occurs frequently in patients with both congenital and acquired immunodeficiency. AIDS-related PCL occurs with a similar distribution across all transmission risk groups and ages, and the tumors are characteristically high-grade diffuse large B-cell or immunoblastic NHL (10). PCL primarily occurs in individuals with a CD4 count of less than 50 cells/mm3, and the improvement in CD4 counts in the HAART era is currently believed to be directly responsible for the decreased incidence of PCL (6). The presence of Epstein Barr virus (EBV) is a universal feature of AIDS-associated PCL; EBV is not found in other PCL (11,12). In the presence of a PCL-related mass in the central nervous system, detection of EBV in the cerebrospinal fluid (CSF) by DNA polymerase chain reaction (PCR) has a sensitivity of 83–100% and a specificity greater than 90% (13–16).
Registry linkage studies confirm a 3600-fold higher relative risk of PCL among individuals living with AIDS than the baseline rate in the general population (17), a likely consequence of the brain representing a reservoir of active viral replication (18). Shortly after the introduction of HAART, a decline in the incidence of AIDS-related PCL was observed by many clinicians, and a meta-analysis of 48 000 individuals confirmed this decrease (relative risk in the HAART versus the pre-HAART era = 0.42, 99% confidence interval [CI] = 0.24 to 0.75) (6).
We therefore wished to examine the longer-term influence of HAART and its different components on the incidence and outcome of PCL. We also investigated and compared the clinicopathologic and treatment-related features of patients who were diagnosed with confirmed and presumptive PCL, before and since the introduction of HAART. The HAART era is defined as the time from which the therapy became routinely available at our institution, and many others, on January 1, 1996.
We identified all HIV-positive individuals (n = 9621) who have attended the Chelsea and Westminster hospital since routine prospective data collection commenced on 1986. At our institution, the diagnostic algorithm for the management of cerebral mass lesions in HIV-seropositive patients has included a 2-week trial of antitoxoplasmosis therapy (1 g of sulphadiazine four times a day and 75 mg of pyrimethamine once a day). Patients who fail to respond to this therapy are offered further diagnostic procedures, either a brain biopsy, or, since 1994, a diagnostic lumbar puncture, if there are no contraindications. The CSF is examined for EBV DNA by PCR as previously described (19), and an EBV-positive brain biopsy or lumbar puncture confirms a diagnosis of PCL, whereas failure of antitoxoplasma treatment without further diagnostic intervention is classified as a presumptive diagnosis of PCL.
Since January 1, 1986, 61 patients in our cohort have been diagnosed with PCL: 39 before January 1, 1996 (the pre-HAART era, N = 3748, 13 205 patient-years), and 22 from January 1, 1996, to October 31, 2005 (the HAART era, N = 5873, 17 651 patient-years). The incidence of PCL in the cohort decreased significantly in the HAART era (1.2 cases per 1000 patient-years, 95% CI = 0.8 to 1.9) compared with the pre-HAART era (3 cases per 1000 patient-years, 95% CI = 2.1 to 4.0; P<.001).
We compared the clinicopathologic features of the patients who were diagnosed in the pre-HAART and the HAART eras (Table 1). Of 22 patients who were diagnosed with PCL in the HAART era, 16 were taking retroviral agents at the time of diagnosis and two individuals had undetectable HIV type 1 plasma viral loads. The majority of patients had CD4 counts of less than 50 cells/mm3. In the HAART era, statistically significantly fewer patients had prior AIDS-defining illnesses than in the pre-HAART era (64% versus 90%; P = .013), and patients were more likely to have the diagnosis confirmed histologically or by CSF PCR (77% versus 26%; P<.001). There were no differences in sex, age, median CD4 cell count, the number of patients with a CD4 count of less than 50 cells/mm3, Eastern Co-operative Oncology Group (ECOG) performance status, interval from HIV diagnosis to PCL diagnosis, or treatment for PCL.
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The median survival for all 61 PCL patients was 1.3 months; the 6- and 12-month overall survival rates were 14% (95% CI = 5 to 23%) and 5% (95% CI = 0 to 12%). We observed a statistically significant, although modest, improvement in overall survival in the HAART era compared with the pre-HAART era (Fig. 1; P = .032); The median survival in the pre-HAART era was 32 days (range = 5–315 days) and the 6- and 12-month overall survival rates were 8% (95% CI = 0 to 17%) and 4% (95% CI = 0 to 12%), whereas the median survival in the HAART era was 48 days (range = 15–1136 days) and the 6- and 12-month overall survival rates were 18% (95% CI = 1 to 34%) and 12% (95% CI = 0 to 26%). Treatment with chemotherapy or radiotherapy was associated with a longer overall survival (P<.001); however, this was confounded because patients who were treated with chemotherapy or radiotherapy in the HAART era had higher ECOG performance scores than patients in the pre-HAART era (P<.001). There were no differences in overall survival by the method of PCL diagnosis or prior AIDS-defining illness. Although it could be considered that some of the improvement in the HAART era may be due to the effects of HAART on reducing opportunistic infections, the effects of HAART on opportunistic infections were not considered relevant due to the short median survival for the whole cohort of 1.3 months. All patients in our cohort died from PCL, except one who was diagnosed in the HAART era who died from cytomegalovirus colitis.
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Because antiretroviral agents with differing CSF penetrations have emerged over the last 10 years as standard constituents of HAART (20), we examined the crude proportions of patients who were diagnosed with PCL in the pre-HAART or HAART eras and who had used a given type of antiretroviral agent ever (Table 2). We had 90% power to detect an 8% difference in magnitude at a 5% significance level; there were no differences that approached statistical significance in the incidence of PCL according to exposure to any specific antiretroviral agent or class of antiretroviral agent in either the pre-HAART or HAART eras. This is consistent with recent data that demonstrate a lack of class effect of antiretroviral agents in the prevention (or treatment) of systemic AIDS-related NHL (9) and AIDS-related Kaposi's sarcoma (21,22).
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In immunocompetent individuals with PCL, a median survival of 4 months has recently been reported with no consistent improvement in the last 30 years (23). The prognosis of AIDS-associated PCL is dismal; the median survival period is generally quoted as 2–3 months, although the point from which it is measured varies, and not all patients are included in some series (24,25). The very poor overall survival in our study may in part be explained by the measurement of survival from confirmed diagnosis or completion of unsuccessful antitoxoplasmosis therapy (26). In other studies, the onset of symptoms, which favorably influences survival duration, has been used in survival analysis (24). Another factor that may relate to the poor survival documented here is the inclusion of all patients with confirmed or presumptive PCL in the HIV-seropositive database without any patient selection. In other series, only treated patients (27,28) or those with confirmed diagnoses (29) have been included. Despite this inclusion, we observed a statistically significant improvement in overall survival in the HAART era, a likely consequence of HAART-induced overall improvements in immune function that appears to confer benefit to the central nervous system.
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Manuscript received March 5, 2006; revised May 1, 2006; accepted May 17, 2006.
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