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HIV Infection Itself May Not Be Associated With Subclinical Coronary Artery Disease Among African Americans Without Cardiovascular Symptoms
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Jnl of the Am Heart Ass March 2016 - Hong Lai, PhD; Richard Moore, MD; David D. Celentano, ScD; Gary Gerstenblith, MD; Glenn Treisman, MD; Jeanne C. Keruly, MS;
Thomas Kickler, MD; Ji Li, MD; Shaoguang Chen, MS; Shenghan Lai, MD; Elliot K. Fishman, MD
"The effect of cocaine use on subclinical atherosclerosis might be stronger than traditional cardiovascular risk.....our results..... did not find evidence for an independent association between HIV infection and subclinical coronary atherosclerosis.....Our study shows that traditional cardiovascular risk profile was significantly associated with the presence of subclinical atherosclerosis. This finding is consistent with other published data.....long-term exposure to ART may increase the risk for subclinical coronary atherosclerosis [from Jules: in this study participants were 59% on PIs, 34% on NNRTIs, no integrase use. This study was conducted between Between June 2004 and February 2015 so subjects had a history of old PIs use. At CROI 2017 D:A:D reported Reyataz/r was NOT associated with CVD http://www.natap.org/2017/CROI/croi_68.htm. Although DAD found DRV associated with increased risk a poster presented subsequently at ACTHIV Conference in april 2017 reported that a pooled analysis of 19 Janssen studies did not indicate increased CVD risk over 6 years use http://www.natap.org/2017/HIV/042617_01.htm - we have yet to have long term CVD risk studies in integrase use]....in our current study, with a sample size over 5 times larger than that in our earlier study, we have found that the associations between HIV infection and subclinical coronary atherosclerosis may be attributed to a markedly worse cardiovascular risk profile in the HIV infected compared to the HIV uninfected....The results in Table 6 show that long-term use of ART may not impose significant risk of subclinical coronary atherosclerosis in those who never used cocaine, whereas the adverse effect of long-term ART use on subclinical coronary atherosclerosis is very apparent in chronic cocaine users.
.......It is critically important to emphasize that despite the fact that an overall nonsignificant association between HIV infection and subclinical coronary atherosclerosis was observed, the findings of this study should not be interpreted as evidence against existence of the adverse cardiovascular consequences of HIV infection"
CONCLUSIONS: "These limitations notwithstanding, our findings may have important implications for the prevention of HIV/ART-associated CAD, especially in AAs. This study revealed a high prevalence of subclinical coronary atherosclerosis in AAs without cardiovascular symptoms, that CAD risk profiles are more adverse in AAs with HIV infection than in HIV uninfected, that long-term exposure to ART may increase the risk for subclinical coronary atherosclerosis, especially in chronic cocaine users, and that HIV infection per se may have no appreciable impact on subclinical coronary atherosclerosis in this population. Although our findings should be regarded as tentative and replication in other cohorts is needed, they suggest that it will be particularly important to prevent and retard coronary atherosclerosis, to aggressively manage traditional risk factors for coronary atherosclerosis in HIV-infected patients who will be receiving potentially long durations of ART, and that abstinence from cocaine or reduced cocaine use in HIV-infected individuals must be one of the highest priorities for preventing HIV/ART-associated coronary atherosclerosis."
"Prevalence of subclinical coronary atherosclerosis reported in this study was different from other published data....Unlike our results, which did not find evidence for an independent association between HIV infection and subclinical coronary atherosclerosis, Post et al. found a significant association between HIV infection and coronary plaque (adjusted PR for age, race, CT scanning center, and cohort) was 1.14 (95% CI, 1.05, 1.24; P=0.001).....The effect of cocaine use on subclinical atherosclerosis might be stronger than traditional cardiovascular risk. ......Our study also demonstrated that the adverse effects of long-term ART use may be modified by cocaine use. The results in Table 6 show that long-term use of ART may not impose significant risk of subclinical coronary atherosclerosis in those who never used cocaine, whereas the adverse effect of long-term ART use on subclinical coronary atherosclerosis is very apparent in chronic cocaine users.....Our data suggest that cocaine use is ...... a risk factor for subclinical atherosclerosis in HIV-infected persons, especially in those with long-term exposure to ART.
........More-detailed analyses revealed that duration of ART use in HIV infected modified the overall association between HIV infection and subclinical coronary atherosclerosis-compared to those without HIV infection, those who were HIV infected and ART naïve were at significantly lower risk for the presence of any coronary stenosis, noncalcified plaque, and subclinical CAD (Table 3, I. comparing those HIV infected ART naïve with HIV uninfected); however, those who were HIV infected and had used ART ≥36 months were at significantly higher risk for the presence of any coronary stenosis (Table 3, III. comparing those HIV infected and ART use ≥36 months with HIV uninfected). These results may partly explain why no significant overall association was found between HIV infection and the presence of subclinical coronary atherosclerosis. The diametrically opposite effects of HIV infection for those who were ART naïve and those who had used ART for ≥36 months cancelled one another out, yielding an overall nonsignificant association between subclinical coronary atherosclerosis and HIV infection in the study population....It is critically important to emphasize that despite the fact that an overall nonsignificant association between HIV infection and subclinical coronary atherosclerosis was observed, the findings of this study should not be interpreted as evidence against existence of the adverse cardiovascular consequences of HIV infection"
[from Jules: first, this study looked at cocaine users vs non-users BUT the definition of non users was not having used in the past 5 years meaning that if participants had previously used cocaine 5 or more years ago the affects on CVD could interfere in the outcome of this study. The comparator s=group should be people who NEVER used cocaine ever.]
"Prevalence of subclinical coronary atherosclerosis reported in this study was different from other published data. Lo et al. compared 78 HIV-infected men with 32 HIV-uninfected men with similar demographic and CAD risk factors, and found that the prevalence of coronary atherosclerosis was higher in HIV-infected men than in non-HIV-infected men (59% vs 34%; P=0.02).10 In previous studies reported by our group, prevalences of any coronary stenosis were similar by HIV status.6, 7, 8, 9, 11, 12, 13 In Post et al., the prevalence of coronary plaque in men was dramatically higher at 76% (77.6% in HIV infected vs 74.4% in HIV uninfected)14 than in our current study, where the prevalence in men is 30%.
Unlike our results, which did not find evidence for an independent association between HIV infection and subclinical coronary atherosclerosis, Post et al. found a significant association between HIV infection and coronary plaque (adjusted PR for age, race, CT scanning center, and cohort) was 1.14 (95% CI, 1.05, 1.24; P=0.001).14 There are several possible explanations for this difference. Probably the most significant difference is that noncalcified plaque in Post et al.14 was defined as "any discernible structure that could be clearly assignable to the vessel wall, ...", whereas in our current study, noncalcified plaque had to be at least 1 mm2 in size. Thus, the prevalence of noncalcified plaque in Post et al. (60%) was much higher than that in this study (only 20%). The CAD risk factor profile of the participants in these 2 studies also differed. For example, the mean age of participants in Post et al. was 53.2 (±6.5) years for HIV infected and 55.8 (±7.4) years for HIV-uninfected, compared to a mean age of our study participants of 45.6 (±7.9) years for HIV infected and 44.2 (±6.9) years for HIV uninfected. Consistent with their older age, study participants in Post et al. also had much more adverse CAD risk profiles than did ours. These differences may also explain why coronary plaque, especially noncalcified plaque, was more prevalent in the Post et al. study."
Effect of Cocaine Use on the Associations Between Long-Term ART Use (≥36 Months) and Subclinical Coronary Atherosclerosis in HIV-Infected Participants
Associations between cocaine use and subclinical coronary atherosclerosis by cocaine use status (never use vs chronic use) are shown in Table 6. By univariable Poisson regression analyses, compared to those who were ART naïve, those who had never used cocaine and had used ART ≥36 months were at significantly higher risk for CAC, coronary stenosis, calcified plaque, and subclinical CAD, whereas chronic cocaine users who had used ART ≥36 months were at significantly higher risk for the presence of CAC, coronary stenosis, noncalcified plaque, calcified plaque, and subclinical CAD. However, after controlling for propensity score, multivariable Poisson regression analyses showed that compared to those who were ART naïve, those who had never used cocaine and had used ART ≥36 months were not at significantly higher risk for any CT outcome variables, whereas chronic cocaine users who had used ART ≥36 months were at significantly higher risk for the presence of coronary stenosis (the propensity score-adjusted PR, 1.87; 95% CI, 1.19, 2.94; P value, 0.007), noncalcified plaque (the propensity score-adjusted PR, 2.46; 95% CI, 1.30, 4.66; P value, 0.006), and subclinical CAD (the propensity score-adjusted PR, 1.62; 95% CI, 1.17, 2.35; P value, 0.011; Table 6).
Discussion
The findings of this study demonstrate that (1) cardiovascular risk profile measured by cardiovascular risk score based on the 2013 ACC/AHA Guideline was significantly associated with the presence of subclinical coronary atherosclerosis, (2) cardiovascular risk profiles were significantly worse in HIV-infected than in HIV-uninfected persons, (3) this study did not find any evidence for an independent association between HIV infection and subclinical coronary atherosclerosis when all HIV-infected participants as 1 group were compared with HIV uninfected, (4) duration of ART use in HIV-infected modified the overall association between HIV infection and subclinical coronary atherosclerosis, (5) cocaine use was independently associated with subclinical coronary atherosclerosis, and (6) the magnitude of long-term ART exposure-associated risk depended on cocaine use status.
Our study shows that traditional cardiovascular risk profile was significantly associated with the presence of subclinical atherosclerosis. This finding is consistent with other published data.15
Our results also show that traditional cardiovascular risk profiles were worse in the HIV infected than HIV uninfected in this population. Nevertheless, given the limitations of data from observational studies, in which selection bias is not avoidable, we treated traditional cardiovascular risk profile as a covariate because the purpose of this investigation was to examine whether HIV infected per se influenced subclinical coronary atherosclerosis.
Prevalence of subclinical coronary atherosclerosis reported in this study was different from other published data. Lo et al. compared 78 HIV-infected men with 32 HIV-uninfected men with similar demographic and CAD risk factors, and found that the prevalence of coronary atherosclerosis was higher in HIV-infected men than in non-HIV-infected men (59% vs 34%; P=0.02).10 In previous studies reported by our group, prevalences of any coronary stenosis were similar by HIV status.6, 7, 8, 9, 11, 12, 13 In Post et al., the prevalence of coronary plaque in men was dramatically higher at 76% (77.6% in HIV infected vs 74.4% in HIV uninfected)14 than in our current study, where the prevalence in men is 30%.
Unlike our results, which did not find evidence for an independent association between HIV infection and subclinical coronary atherosclerosis, Post et al. found a significant association between HIV infection and coronary plaque (adjusted PR for age, race, CT scanning center, and cohort) was 1.14 (95% CI, 1.05, 1.24; P=0.001).14 There are several possible explanations for this difference. Probably the most significant difference is that noncalcified plaque in Post et al.14 was defined as "any discernible structure that could be clearly assignable to the vessel wall, ...", whereas in our current study, noncalcified plaque had to be at least 1 mm2 in size. Thus, the prevalence of noncalcified plaque in Post et al. (60%) was much higher than that in this study (only 20%). The CAD risk factor profile of the participants in these 2 studies also differed. For example, the mean age of participants in Post et al. was 53.2 (±6.5) years for HIV infected and 55.8 (±7.4) years for HIV-uninfected, compared to a mean age of our study participants of 45.6 (±7.9) years for HIV infected and 44.2 (±6.9) years for HIV uninfected. Consistent with their older age, study participants in Post et al. also had much more adverse CAD risk profiles than did ours. These differences may also explain why coronary plaque, especially noncalcified plaque, was more prevalent in the Post et al. study.
In contrast, both studies found that HIV infection was not significantly associated with the presence of calcified plaque. In Post et al., the unadjusted PR for calcified plaque by HIV infection was 0.88 (95% CI, 0.73, 1.06; P=0.19; based on the data in Table 2, 14), and adjusted PR was 1.05 (95% CI, 0.88, 1.27; P=0.58). In this study (men only), the unadjusted PR for calcified plaque stenosis by HIV infection was 1.08 (95% CI, 0.83, 1.41; P=0.55), and the adjusted PR was 1.02 (95% CI, 0.76, 1.37; P=0.89). In the earlier study by Lai et al.,12 a significant association was found between cocaine and CAC, the magnitude of which was similar to that of our current study. However, unlike our current study, there was also an independent association found between HIV infection and CAC in AAs. Associations with coronary plaque and stenosis were not assessed in our earlier study. We cannot account for the difference in results regarding HIV infection and CAC prevalence between our earlier and our current study. The demographics of the sample were similar as was the CAD risk profiles and prevalence of CAC. Nonetheless, in our current study, with a sample size over 5 times larger than that in our earlier study, we have found that the associations between HIV infection and subclinical coronary atherosclerosis may be attributed to a markedly worse cardiovascular risk profile in the HIV infected compared to the HIV uninfected. Thus, after controlling for confounding factors, especially propensity score, some significant associations identified in the univariate analyses diminished.
It is critically important to emphasize that despite the fact that an overall nonsignificant association between HIV infection and subclinical coronary atherosclerosis was observed, the findings of this study should not be interpreted as evidence against existence of the adverse cardiovascular consequences of HIV infection. More-detailed analyses revealed that duration of ART use in HIV infected modified the overall association between HIV infection and subclinical coronary atherosclerosis-compared to those without HIV infection, those who were HIV infected and ART naïve were at significantly lower risk for the presence of any coronary stenosis, noncalcified plaque, and subclinical CAD (Table 3, I. comparing those HIV infected ART naïve with HIV uninfected); however, those who were HIV infected and had used ART ≥36 months were at significantly higher risk for the presence of any coronary stenosis (Table 3, III. comparing those HIV infected and ART use ≥36 months with HIV uninfected). These results may partly explain why no significant overall association was found between HIV infection and the presence of subclinical coronary atherosclerosis. The diametrically opposite effects of HIV infection for those who were ART naïve and those who had used ART for ≥36 months cancelled one another out, yielding an overall nonsignificant association between subclinical coronary atherosclerosis and HIV infection in the study population.
In previous literature, the associations between HIV infection and subclinical coronary atherosclerosis was rarely analyzed by duration of ART use. Thus, the associations derived from those studies may not be associations between HIV infection itself and subclinical coronary atherosclerosis. Further studies, especially longitudinal studies, are required to corroborate our results and investigate whether and why those who were HIV infected but ART naïve may have a lower risk of subclinical coronary atherosclerosis than HIV uninfected.
Notably, most of the ART use in our cohort was protease inhibitor (PI)-based, with little non-nucleoside reverse transcriptase inhibitor person time (Table 1) and not use of the newer integrase inhibitors. The D:A:D study also found an association between duration of PI use and clinical MI.2 Incidence of MI increased from 1.53 per 1000 person-years in patients not exposed to PIs to 6.01 per 1000 person-years among patients exposed to PIs for >6 years [from Jules: this study was in 2007. DAD study at CROI 2017 found Reyataz/r was not associated with CVD]. In another study, the relative hazard of MI was 0.8 (95% CI, 0.5-1.3) for men exposed to PI for <18 months, 1.5 (95% CI, 0.8-2.5) for men exposed for 18 to 29 months, and 2.9 (95% CI, 1.5-5.0) for men exposed for ≥30 months.3 Our results may be demonstrating the role of ART, and specifically PIs, in promoting subclinical coronary atherosclerosis. There is some evidence suggesting that ART may improve endothelial dysfunction in a short term; however, long-term exposure to ART may worsen endothelial dysfunction.22, 23, 24 Further studies are also needed to confirm these results.
Our study showed that cocaine use was independently associated with subclinical coronary atherosclerosis. This finding is consistent with other published data.9, 12, 13 In our study, those who were HIV infected and ART naïve had a higher traditional cardiovascular risk than those without HIV infection, those without HIV infection had used cocaine significantly more commonly and had used cocaine significantly longer than those who were HIV infected and ART naïve (Table 7). Notably, the adverse effects association of long-term ART use with subclinical atherosclerosis was only found in cocaine users, but not in those who never used cocaine. The effect of cocaine use on subclinical atherosclerosis might be stronger than traditional cardiovascular risk.This finding highlights the importance of reducing cocaine use in HIV-infected persons, especially in those who are on ART. Because ART is a lifelong treatment that improves survival in those with HIV infection, our finding suggests that reduced cocaine use must be one of highest priorities in fight against HIV/ART-associated comorbidities.
Our study also demonstrated that the adverse effects of long-term ART use may be modified by cocaine use. The results in Table 6 show that long-term use of ART may not impose significant risk of subclinical coronary atherosclerosis in those who never used cocaine, whereas the adverse effect of long-term ART use on subclinical coronary atherosclerosis is very apparent in chronic cocaine users. These findings strongly suggest that it is critically important to treat cocaine addiction in HIV-infected cocaine users because long-term ART use may be necessary to control HIV disease. Our data suggest that cocaine use is not only a risk factor for HIV transmission, but also a risk factor for subclinical atherosclerosis in HIV-infected persons, especially in those with long-term exposure to ART. Thus, treating cocaine addiction must be a high priority for managing HIV disease and preventing HIV/ART-associated subclinical and clinical CAD in HIV-infected AAs.
Unfortunately, there are no US Food and Drug Administration-approved medications to treat cocaine addiction. Some studies suggest that transcranial magnetic stimulation of the dorsolateral prefrontal cortex or even cash-based incentive intervention may reduce cocaine use.25, 26 Further studies are needed to confirm these findings.
Our study has several strengths that should be mentioned: (1) Our study was performed in 1 medical center and 1 ethnic group. Thus, the effects of race or study site could not confound the findings of this study; (2) by employing the propensity score approach, the findings from this study should be more robust to potential hidden bias from unobserved confounding factors; and (3) our study only included participants without clinical CAD.
Nevertheless, our study also has several important limitations: (1) This investigation is a cross-sectional study, and although we explored whether HIV was associated with the presence of subclinical coronary atherosclerosis, in essence we had no knowledge as to whether or not subclinical coronary atherosclerosis was present before the HIV infection; (2) our study was conducted in an inner-city AA population. Approximately 75% of the study participants were cocaine users, and nearly all used alcohol. However, the prevalences of more-traditional risk factors were still considerably low. The results therefore may not be generalizable to other populations without exercising caution; (3) this study did not collect diet data on all study participants; (4) our study did not take into account the effects of other viral infections on subclinical coronary atherosclerosis; (5) this study could not include those with chronic kidney failure. Thus, the results may not be generalized without caution; (6) given that those who were on ART longer may have also had HIV-infection longer, because in a cross-sectional study it is impossible to separate the adverse effect of HIV infection from the effect of ART. For example, whereas DAD data suggest that ART plays a role, the SMART study clearly shows that HIV plays a larger role. Thus, to some extent, ART duration may be more a marker for HIV duration than for ART itself. Longitudinal studies are needed to address these important issues; and (7) based on our definition of never using cocaine, cocaine never users may have included "remote users," who had used cocaine 5 years before the enrollment of this investigation. However, this exposure misclassification error should be minimal given that (1) according to our longitudinal observations, few chronic cocaine users quit, and (2) this exposure misclassification error should be nondeferential.
Conclusions
These limitations notwithstanding, our findings may have important implications for the prevention of HIV/ART-associated CAD, especially in AAs. This study revealed a high prevalence of subclinical coronary atherosclerosis in AAs without cardiovascular symptoms, that CAD risk profiles are more adverse in AAs with HIV infection than in HIV uninfected, that long-term exposure to ART may increase the risk for subclinical coronary atherosclerosis, especially in chronic cocaine users, and that HIV infection per se may have no appreciable impact on subclinical coronary atherosclerosis in this population. Although our findings should be regarded as tentative and replication in other cohorts is needed, they suggest that it will be particularly important to prevent and retard coronary atherosclerosis, to aggressively manage traditional risk factors for coronary atherosclerosis in HIV-infected patients who will be receiving potentially long durations of ART, and that abstinence from cocaine or reduced cocaine use in HIV-infected individuals must be one of the highest priorities for preventing HIV/ART-associated coronary atherosclerosis.
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