After adjusting for age, race and educational status and independent of other cofactors including stimulant use, 10-year increase in ART adherence corresponded with four-fold improvement in CD4+/CD8+ ratios across time among HIV+ ART-using participants in the MACS. As predicted, we found negative, small associations between reported use of cocaine or methamphetamine and CD4+/CD8+ ratios as well as cumulative rates of medical visits for HIV+ men. Among HIV- MACS participants, significant, but small associations were detected between CD4+/CD8+ ratios with cumulative medical, cumulative number of male sexual partners and cigarette pack years..
The clinical relevance of these findings for HIV-seropositive men using ART is that the unique contributions to associations of methamphetamine and cocaine with their CD4+/CD8+ ratios, while statistically significant, are small and clinically not meaningful. However, large and positive associations existed between measures of ART adherence and immune function. We know of no simple explanation why individual markers of CD4+ and CD8+ failed to be associated significantly with any of the predictors, though our solutions, even when transforming these values using logarithmic functions, was non-significant.
The model used in these analyses provided different results from an earlier report [6
], which found no association with measures of CD4+, CD8+ and their ratio for MACS participants when contrasting each level of use of a range of substances (i.e., daily, weekly, monthly use) to nonuse. The analytic approach in this report, the “recovery” approach, was devised to capture associations between stimulant drugs and immune functioning over a period that minimized influence of missing observations, i.e., 5 visits or 2.5 years. The method captured associations between stimulants and immune functioning during relevant periods of use in the 6 month intervals and also allowed for the immune system to recover during periods of absence of use. In data not shown, a 2-visit cumulative model (or data over 1 year) was conducted, which yielded outcomes in which confidence intervals overlapped completely. The 5 visit model had narrower confidence intervals, providing more stable outcomes due to less missing data. In these MACS data, this “recovery” approach using a rolling 2.5 year window for analysis retains an emphasis on proximal associations between stimulant use/nonuse and immune biomarkers and observes their movement through time.
It is comforting that our findings showed expected negative associations between methamphetamine and cocaine use and immune functioning, particularly in HIV+ men. Methamphetamine [17
] and cocaine [3
] increase HIV replication in-vitro; both also show dose-response associations in frequency of use and levels of neopterin, a marker of immune activation that characterizes HIV-disease progression [18
]. What is not clear is whether the large associations observed between adherence to ART and CD4+/CD8+ ratios, even in the context of stimulant use, is consistent with a recent review showing that non-injection users of a range of illicit drugs accelerated development of an AIDS defining event [19
]. Indeed, while the adherence measure in our report is likely an underestimate of actual medication adherence, which implies the potential for even stronger associations between ART adherence and immune function than observed. It is of note that we found no parallel associations between stimulant use-years and CD4+/CD8+ cell ratios for HIV- men, which may imply a general capacity of the immune system to rebound from acute stimulant use-associated insults in HIV-uninfected men.
Two unexpected findings were observed in HIV- men. HIV- men who reported higher cumulative numbers of male sexual partners showed significantly lower log CD4+/CD8+ ratios. We can think of no biologic mechanism for this finding. Second, among HIV- men higher numbers of pack/years of cigarettes associated strongly with higher ratios of CD4+/CD8+. This is consistent with previous studies that have shown smoking to be correlated with an increase in CD4+ cell counts among HIV- individuals [20
]. The lack of association of cigarette smoking on CD4+/CD8+ ratio among HIV+ ART-using individuals reflects a mixed literature, with some studies showing an association between smoking and CD4+ count decline and other studies showing no association.
Findings in this report are limited to HIV+ ART-using men with histories of stimulant use. It is possible that HIV+ ART-using men who are assayed during periods of acute use of stimulants would show stronger negative associations with markers of immune function, particularly in light of earlier work [10
], that would not be detected using analyses that rely on an extensive observation period. As in any cohort study, there may be a lead-time bias such that one cannot control or measure important drug-related use events that may have occurred before participants joined the cohort.
The strongest correlate of CD4+/CD8+ ratios was cumulative ART adherence among HIV+ MACS participants. These findings provide support to clinicians who are considering the value of sustained ART regimens to maintain immune and general health functioning among HIV+ men who report stimulant use. In light of the limitations that adherence levels reported are likely underestimates, there may be clear health benefits to the immune function of patients known by their clinicians to use cocaine or methamphetamine to access interventions that enhance ART adherence.