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Associations between antiretroviral use and subclinical coronary atherosclerosis.....
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"the implications of these findings may include that the types of ART used do not comprise a distinct substantial risk for coronary plaque presence or extent......these findings support the hypothesis that ART type is a less important determinant of CVD risk than achievement and maintenance of HIV virology suppression......our findings support the assertion that virologic suppression achieved through ART use may outweigh or even offset any potential negative impact of individual or combination ART on coronary atherogenesis or its predisposing conditions......In this group of aging, virally suppressed HIV-infected men with extensive protease inhibitor exposure, no consistent associations between protease inhibitor use and subclinical coronary plaque presence and extent were apparent......inferences between darunavir use and coronary plaque risk are not possible from these data alone"
AIDS 2016 - Thomas, Guajira P.; Li, Xiuhong; Post, Wendy S.; Jacobson, Lisa P.; Witt, Mallory D.; Brown, Todd T.; Kingsley, Lawrence A.; Phair, John P.; Palella, Frank J. Jr.
To further explore the characteristics of men exposed to zidovudine and darunavir (the two antiretroviral drugs the use of which demonstrated the most significant associations with coronary plaque), we examined differences in HIV variables between men who were exposed compared with men who were naive to each of these drugs. We found that men who received zidovudine and men who received darunavir had longer median durations of HIV infection, lower median CD4+ cell counts at the time of HAART initiation, and a higher percentage of visits with detectable HIV RNA (>50 copies/μl) compared with men who had not received these medications (Table S2, Supplemental Digital Content 2, http://links.lww.com/QAD/A964).
In this very well characterized, longitudinally followed group of aging HIV-infected men, the presence and extent of subclinical coronary plaque was inconsistently linked to the use of antiretroviral therapy, either specific drugs, or drug classes. When associations between cumulative use of ART and plaque were found, they in general involved modest effect sizes and marginal statistical significance for either plaque presence or plaque extent but not both. The HIV-infected participants were, in general, a group that was durably virologically suppressed while receiving combination ART. Although we did not have available for comparison a sizable group of HIV-infected persons who were not receiving ART, the implications of these findings may include that the types of ART used do not comprise a distinct substantial risk for coronary plaque presence or extent. Furthermore, these findings support the hypothesis that ART type is a less important determinant of CVD risk than achievement and maintenance of HIV virologic suppression, a factor known to be associated with avoidance of adverse cardiovascular clinical outcomes [15,16]. In this context, our findings support the assertion that virologic suppression achieved through ART use may outweigh or even offset any potential negative impact of individual or combination ART on coronary atherogenesis or its predisposing conditions.
We found that cumulative use of the TANRTI zidovudine was significantly associated with increased extent of total plaque score and mixed plaque; also with presence and extent of noncalcified plaque with borderline statistical significance. Although positive associations between use of TANRTIs and increases in traditional CVD risk factors have been reported extensively in the literature, we found no significant associations between stavudine, the other commonly used TANRTI, and coronary plaque, raising the question of a possibly unique risk conferred by zidovudine use that might be distinct from the class effects of TANRTIs. Alternatively, these associations might be a surrogate marker for longer duration of HIV infection, including more prolonged exposure to unsuppressed HIV viral replication among persons exposed to zidovudine.
We found a limited positive association between abacavir use and presence, but not extent, of noncalcified plaque. The existing literature on the association between abacavir and CVD is extensive, conflicting, and not yet conclusive [26]. Moreover, reported associations between abacavir use and risk for MI suggest that MI risk is associated with very recent abacavir use (usually within 6 months of use), implying that if such an effect exists, it may be reversible with discontinued use of the drug [27]. Furthermore, a hypothesized mechanism by which abacavir use may be linked to MI risk involves a net positive effect upon intravascular platelet activation, also potentially reversible and thereby not necessarily reflected in coronary plaque burden [28].
In this group of aging, virally suppressed HIV-infected men with extensive protease inhibitor exposure, no consistent associations between protease inhibitor use and subclinical coronary plaque presence and extent were apparent. Cumulative darunavir use was associated with a substantial increase in prevalence of calcified plaque and extent of CAC and total plaque score among the relatively few studied men (n = 90) who were darunavir-exposed. Given this small sample size, as evidenced by the broad CIs, our measurement of the effect size is probably not precise, and inferences between darunavir use and coronary plaque risk are not possible from these data alone. Also, the associations might reflect the effect of longer duration of HIV infection and unsuppressed HIV viremia among darunavir-exposed men compared with nondarunavir-exposed men. In support of this interpretation, unlike some of the older protease inhibitors, darunavir use has not, per se, been demonstrated to constitute a distinct association with factors known to increase CVD risk in the general population, such as proatherogenic hyperlipidemia or insulin resistance [29,30]. Furthermore, in the absence of clinical outcome data linking darunavir to increased CVD events, our findings regarding association of its use with greater prevalence and amount of specific plaque types among the relatively small number of darunavir users in our cohort need to be interpreted with caution.
As was demonstrated in the Strategies for Management of Antiretroviral Therapy trial, the benefits of continuous ART-related HIVsuppression (and possibly immune repletion), regardless of the ART drugs used probably far outweigh any deleterious or CVD-predisposing effects of any specific ART use that might be mediated through classic CVD risk factors [16]. HIV nonsuppression is clearly associated with greater levels of systemic inflammation and adverse immune activation [7,31], processes that have been linked to coronary atherogenesis in the general population [32]. ART-induced HIV RNA suppression reduces systemic inflammation and immune activation, which in turn may decrease risk for coronary atherogenesis and/or plaque progression [31].
Our current findings suggest that overall exposure to specific antiretroviral therapies is unlikely to be a significant driver of these associations. HIV parameters including CD4+ nadir, CD4+ cell count and levels of inflammatory biomarkers have been found to be independent risk factors for CVD among HIV-infected individuals, suggesting that HIV infection itself contributes to CVD risk [35]. The association between duration of HAART use and coronary stenosis recently reported by our group [4] may indicate that HAART use duration is a surrogate marker for duration of HIV infection and less likely a discreet risk factor for coronary stenosis associated with specific antiretroviral drug use.
Our study has important limitations including the cross-sectional nature of the plaque data and the fact that persons were exposed to many different ART therapies over time that were variably remote from the time of scanning. We attempted to control for confounders using multivariable analysis; however, in this observational nonrandomized study, it is not possible to control for all potentially confounding variables. Also, our study included only MSM, therefore the findings might not be generalizable to women or to all men.
In this group of aging HIV-infected, largely virally suppressed men with extensive exposure to ART, we found no consistent association between the use of specific ART drugs with both the presence and extent of coronary plaque, despite the fact that use of some of the studied drugs has been associated with clinical factors known to increase coronary plaque risk in the general population. We hypothesize that the lack of consistent associations between ART use and plaque presence and extent reflect that the durable benefits of prolonged HIV suppression that ART use affords offset any drug-associated risks for coronary plaque in this population. Future work should include systematic longitudinal evaluation of ART-naive persons who initiate specific ART therapy and assessment for the development and progression of subclinical plaque as well as clinical CVD outcomes.
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