There were 179 incident cases of NHL identified in the MACS between 1984 and 2003, of which 160 had prediagnostic serum available for KSHV DNA assays. Because our intent was to study only AIDS-related B-cell lymphomas, two T-cell lymphomas and three lymphoplasmacytic lymphomas were excluded, leaving 155 lymphomas for this analysis. NHL cases included 50 (32%) primary central nervous system lymphoma, 30 (19%) diffuse large B-cell lymphoma, 23 (14%) immunoblastic lymphoma, 21 (15%) Burkitts lymphoma, and 31 (20%) lymphomas not otherwise specified. None of the cases were classified as primary effusion lymphoma. Characteristics of cases and their matched controls are compared in . NHL cases were significantly more likely to have had KS and to have more advanced HIV disease, as indicated by lower CD4 cell count at study baseline and greater reduction in CD4 cell count over time than their matched controls (each P < 0.05; ).
Characteristics of Incident Non-Hodgkin Lymphoma (NHL) Cases and Matched Controls Among HIV-Infected Men in the Multicenter AIDS Cohort Study (MACS) Between 1984 and 2003
Detection of KSHV DNA in prediagnostic serum was more common among NHL cases than controls (14% versus 6%, P = 0.03). However, among cases and controls who had detectable KSHV DNA, the median KSHV viral load (406 versus 325, P = 0.39) was comparable. Detection of KSHV DNA was no longer significantly associated with odds of NHL (OR, 1.0; 95% CI, 0.39–2.8) after controlling for age, CD4 cell count at baseline, and change in CD4 cell count. Similar results were seen when analysis was restricted to 65 case–control pairs with serum samples within 1 year before diagnosis (), when a higher KSHV DNA copy number threshold (5 or greater or 25 or greater) was considered as positive and when adjustment was made for HIV viral load and EBV serum copy number (data not shown).
Comparison of Detectable KSHV Serum DNA and KSHV Antibodies Among HIV-Positive Incident NHL Cases Compared With HIV-Positive Matched Controls
When men were stratified by history of KS, serum KSHV DNA prevalence was significantly higher among NHL cases than controls among the 254 participants without a history of KS (11% versus 4%, P = 0.04) but was similar among the 54 men with a history of KS (24% versus 25%, P = 0.92). However, KSHV DNA was no longer associated with incident NHL in multivariate analysis among either the 108 case–control pairs without KS (OR, 1.5; 95% CI, 0.30–7.2; ) or in multivariate unconditional logistic regression among the 116 cases and 138 controls without a history of KS (OR, 2.0; 95% CI, 0.60–7.2). When NHL subtype was considered, KSHV DNA was not significantly associated with elevated odds of NHL among the 21 Burkitts lymphomas, the 23 immunoblastic lymphomas, the 50 primary central nervous system lymphoma, or the 30 diffuse large B-cell lymphoma (data not shown).
In this HIV-infected population of MSM, the majority of subjects (79%) had detectable KSHV antibodies () and seropositivity was not associated with NHL (). Among 253 men with KSHV antibody data, seropositivity was common among both the 27 men with and the 226 men without detectable KSHV serum DNA detected (93% and 77%, respectively). History of EBV infection was also common among these men, and having detectable serum EBV DNA was not more common in cases than controls (57% versus 53%, P = 0.45). Odds of KSHV serum DNA detection were not associated with lower CD4 cell count, higher HIV viral load, or serum EBV DNA detection.
Because the 155 NHL cases had more advanced HIV disease than controls matched on duration of HIV infection (), we performed a second case–control study on the subset of 76 NHL cases who developed NHL after AIDS diagnosis (AIDS-NHL) matched to AIDS controls by time since AIDS. Detectable serum KSHV DNA was not more common among AIDS-NHL cases than AIDS controls overall (14% versus 9%, P = 0.32) and was not associated with increased risk of AIDS-NHL ().