In this study of over 3000 HIV-infected patients followed at an inner-city hospital clinic in Baltimore, Maryland, we observed a substantial decline in NHL incidence over an 18-year period. In the HAART era (1996 onward), NHL risk was strongly elevated in subjects who had a low CD4 count or had previously spent several months or more with an elevated HIV viral load. We did not see an association between serum globulin levels and NHL risk.
Our results showing that NHL risk rises sharply with declining CD4 count are in good accord with results from other studies (6
). Although we had too few cases to analyze risk for separate NHL subtypes, prior work demonstrates that the relationship with CD4 count is apparent for the most frequent AIDS NHL subtypes, DLBCL and CNS NHL (6
). EBV is commonly detected in tumor tissue from AIDS-related CNS NHLs (virtually 100% of cases) and DLBCLs (approximately 50%) but not in Burkitt NHL (4
). As observed in our study, the current CD4 count (a marker of present immune status) appears to be as good a marker of NHL risk as nadir CD4 count (16
), and the relationship between CD4 count and NHL risk continues to be important in the HAART era (6
). Although we had no data on the EBV status of our NHL cases, the strong association with CD4 count supports the hypothesis that a major component of AIDS lymphomagenesis can be explained by severe HIV-induced immunosuppression, which allows for EBV reactivation and virus-driven transformation of lymphocytes (5
The effect of HAART in reducing the risk of AIDS associated NHL has been dramatic, with declines of 40-80% comparing NHL incidence in the HAART era to that in the pre-HAART era (3
). Prior studies have also described lower NHL risk in HAART users compared with non-users, with benefits apparent almost immediately and extending over years of HAART use (20
). The mechanism underlying the effectiveness of HAART in reducing NHL risk is presumably related, at least in part, to its ability to lead to improved immune status (i.e., increases in CD4 count) and control of EBV.
As shown in , NHL incidence in this HIV clinic cohort decreased dramatically well before HAART use climbed after 1996. The reason for a decline in NHL incidence before the introduction of HAART is unclear, but it has been noted previously in U.S. national trends among people with AIDS (3
). The temporal decline could partly relate to increasing use by clinicians of moderately effective HIV therapy (i.e., dual nucleoside therapy). After we controlled for the calendar trend in NHL incidence in our proportional hazards model, we were unable to demonstrate a protective effect of HAART on the risk of developing NHL. Nonetheless, the close correlation between calendar year and HAART use led to wide confidence limits for the estimated HAART effect, including the possibility of substantial benefit (i.e., lower limit of 0.6 for the hazard ratio, corresponding to a 40% reduction in NHL risk). As noted above, we lacked detailed information on interruptions in HAART and subjects’ adherence to their regimens. Also, in clinical practice, HAART was prescribed preferentially to patients with more severe immunodeficiency, as indicated by contemporaneous guidelines (e.g., reference (13
)). This pattern of use could have attenuated the apparent benefits attributable to HAART (15
Of note, we observed an increase in NHL risk with increasing prior duration of high-level viremia (i.e., HIV viral load of at least 5.00 log10
copies/ml). NHL risk rose steeply even after only a few months of high-level viremia (multivariable hazard ratios = 2.6-3.4) and increased further with high-level viremia for 1.5 years or more (multivariable hazard ratio = 6.8). These results corroborate those recently reported by Zoufaly et al., who described increasing NHL risk to be independently associated with cumulative HIV viremia among individuals treated with HAART (8
). In that study, the investigators measured cumulative viremia as a product of the log-transformed HIV viral load (regardless of level) and duration. In contrast, we considered only time spent with an HIV viral load of at least 5.00 log10
copies/ml, because our initial analyses indicated that only viremia of this magnitude was associated with elevated NHL risk (). The relationship between viremia and NHL risk could reflect detrimental effects on immune status associated with absence of treatment or incompletely effective HAART. Our analyses showed that this association between duration of high-level viremia and NHL risk was independent of CD4 count, and in general, the effect of HIV replication on AIDS risk is only partly explained by its association with future declines in CD4 count (7
). The association of NHL risk with prolonged uncontrolled viremia may therefore reflect other disturbances of immune function, such as chronic immune activation or direct effects of HIV on B-cells (7
An elevated level of total serum globulin is thought to reflect hypergammaglobulinemia and therefore generalized B-cell activation (11
). In accord with expectation, serum globulin levels in our HIV-infected subjects were higher than observed in healthy individuals (i.e., median 4.2 g/dL vs. 2.0-3.5 g/dL in the general population) (22
). It is difficult to reconcile our null findings relating serum globulin results and NHL risk with those reported by Grulich et al. (9
). However, supporting our negative results, a case-control study found no association between the risk of AIDS NHL and levels of IgG, IgM, IgA, and IgE measured in pre-diagnostic serum specimens (23
). While the inconsistency in association between globulin levels and NHL risk might suggest that B-cell activation is irrelevant in the pathway to NHL, another explanation could be that B-cell activation is important only for some NHL subtypes, or that alternative markers of B-cell activation are required. Along these lines, serum levels of soluble CD30 (a lymphocyte surface molecule) or free immunoglobulin light chains may provide more sensitive methods for assessing B-cell activation (23
We found additional associations between demographic characteristics and NHL risk. Among HIV-infected individuals, higher NHL risks are generally observed in males compared to females, whites compared to non-whites, and with increasing age (16
). Some studies (16
), but not all (8
), have reported an especially elevated risk for NHL among HIV infected MSM. These associations could reflect accumulation of genetic damage with age, differences in exposures to environmental cofactors or socioeconomic status, or the variable presence of an additional causative infectious agent. For example, human herpesvirus 8 is implicated in a minority of DLBCLs (29
), and coinfection with this virus is especially common in HIV-infected MSM. NHL risk could also have been affected by duration of HIV infection or polymorphisms in host immune genes, but we did not have data on these factors. The availability of longitudinal data for a large clinic population, extending into the HAART era, was a strength of our study. We also had access to repeated laboratory measurements over time, which allowed us to thoroughly examine associations between relevant laboratory markers and NHL risk.
In conclusion, our results highlight the continued importance of immunosuppression in the development of NHL among HIV-infected individuals during the HAART era. The increased NHL risk observed with prolonged HIV viremia may reflect the effects of chronic immune activation and could support earlier initiation of HAART to prevent development of this malignancy. Studies utilizing additional markers of B-cell activation would be informative.