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Marijuana use impacts midlife cardiovascular events in HIV-infected men
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"Cardiovascular (CV) disease is a comorbidity of particular concern in HIV+ populations [13], given that the estimated incidence is up to two-fold higher than that of age-matched uninfected controls [14, 15]."
"Heavy marijuana use is a risk factor for CV disease in HIV-infected men ages 40-60, independent of tobacco smoking and traditional risk factors......Furthermore, theincrease in CV events was additive in marijuana/tobacco co-users. These findings suggest that clinicians should consider heavy marijuana smoking as a modifiable risk factor when optimizing preventive care, particularly for individuals already at increased risk......CV event rates were also increased among marijuana users who did not smoke cigarettes compared to non-smokers, and highest among marijuana/tobacco co-users (P <0.01 and P <0.001; Figure 3B, right panel)......In logistic regression models adjusted for age, smoking, viral load, and 2-3 vs. 0-1 traditional CV risk factors, time-updated heavy marijuana use was associated with 2.5-fold increased odds of CV events (95% CI, 1.2-5.3; P =0.016). Effects of marijuana/tobacco co-use on increased odds of CV events were additive in this model (odds ratio 4.8 [95% CI, 1.8-12.7]; P <0.01) (Table 3).
Heavy marijuana use was also associated with elevated WBC count within the normal physiological range, an indicator of systemic inflammation that has been previously associated with increased cardiovascular disease in the general population [32, 33]. Furthermore, this elevation in WBC counts was explained by increased neutrophil counts. Elevated rates of CV events were observed amongHIV+ heavy marijuana users beginning at relatively young ages (< 50 years), and were further increased in marijuana/tobacco co-users compared to usersof only one substance. Further studies are needed to determine whether the effect of long-term heavy marijuana use on CV events is related to pro-inflammatory effects of non-tobacco smoke exposure, non-inflammatory effects (e.g., transient tachycardia and/or hypertension, elevated carboxyhemoglobin, hemodynamic effects, effects on platelets) [22-24], or a combination of these effects."
Clinical Infectious Diseases April 27 2017 - David R. Lorenz1, Anupriya Dutta1, Shibani S. Mukerji1,2, Alex Holman1, Hajime Uno3, and Dana Gabuzda1*
1Department of Cancer Immunology and Virology and 3Department of Population Science, Dana-Farber Cancer Institute, Boston, MA, US; 2Department of Neurology, Massachusetts General Hospital, Boston, MA, USA;
ABSTRACT
Background.
Marijuana use is prevalent among persons infected with HIV, but its long-term effects on HIV disease progression and comorbidities are unknown.
Methods.
A prospective study of 558 HIV-infected men enrolled in the Multicenter AIDS Cohort Study between 1990-2010: 182 HIV seroconverters and 376 with viral suppression on combination antiretroviral therapy (ART). Associations between heavy marijuana use and HIV disease markers or white blood cell (WBC) count were examined using mixed-effects and linear regression models. Effects of marijuana use on cardiovascular (CV) events and other endpoints were estimated by Kaplan-Meier and logistic regression analyses.
Marijuana was the primary exposure of interest. Subjects were classified based on self-reported frequency of marijuana use as heavy users (defined as daily or weekly use at ≥ 50% of biannual visits), non-users (less than monthly or no use at all visits), and occasional users (remaining subjects). Subjects reporting smoking an average of 0.25 cigarette packs/day or more were classified as moderate/heavy tobacco smokers.
Results.
The median baseline age of participants was 41, 66% were white, 79% had education > 12 years, and 20% reported heavy marijuana use at ≥ 50% of biannual visits during follow-up. Long-term heavy marijuana use showed no significant associations with viral load, CD4 counts, AIDS, cancer, or mortality in both cohorts, but was independently associated with increased CV events between ages 40-60 after adjusting for age, tobacco smoking, viral load, and traditional risk factors (odds ratio [OR], 2.5; 95% confidence interval [CI] 1.3, 5.1). Marijuana and tobacco use were each independently associated with higher WBC counts in adjusted models (P<0.01); in turn, the highest quartile of WBC counts (≥ 6500 cells/μL) was associated with increased CV events (OR 4.3; 95% CI, 1.5, 12.9).
Conclusions.
Heavy marijuana use is a risk factor for CV disease in HIV-infected men ages 40-60, independent of tobacco smoking and traditional risk factors.
INTRODUCTION
Marijuana use for recreational and medicinal purposes is prevalent among individuals infected with human immunodeficiency virus type 1 (HIV): recent estimates in cohorts of HIV-infected (HIV+) men who have sex with men (MSM) range from 24% to 62% [1-3]. Despite this high prevalence, few studies have investigated health effects of long-term heavy marijuana use among HIV+ individuals [4]. Observational studies reported contradictory findings regarding associations between marijuana use and HIV viral load [5-9] or CD4 cell counts [1, 3, 5, 6, 10]. Animal model studies also report inconsistent effects of tetrahydrocannabinol administration on viral replication and disease progression [11, 12]. Thus, the effects of marijuana use on HIV disease and associated comorbidities remain unclear.
Cardiovascular (CV) disease is a comorbidity of particular concern in HIV+ populations [13], given that the estimated incidence is up to two-fold higher than that of age-matched uninfected controls [14, 15]. The high prevalence of tobacco smoking and other traditional CV risk factors, combination antiretroviral therapy (ART)-associated dyslipidemia, and health care disparities explain only a portion of this elevated risk [16-21]. Thus, identifying non-traditional risk factors that explain elevated CV risk in HIV-infected populations is a priority for improving health outcomes [13-15]. Marijuana smoking has been associated with myocardial infarction and other adverse cardiovascular events in a few studies of HIV-uninfected individuals [22-25], yet the evidence regarding its effects on cardiovascular disease remains unclear [4]. To our knowledge, its effects on CV disease in HIV+ individuals have been evaluated in only one study [20].
The aims of this longitudinal study were to examine the effect of long-term heavy marijuana use on HIV disease markers in men with acute and chronic HIV infection, and evaluate differences in cardiovascular events and other health outcomes during long-term follow-up.
DISCUSSION
In this longitudinal nested study of HIV+ men on ART, heavy marijuana use was associated with increased rates of CV events in men ages 40-60 independent of cigarette smoking and other known risk factors. Heavy marijuana use was also associated with elevated WBC count within the normal physiological range, an indicator of systemic inflammation that has been previously associated with increased cardiovascular disease in the general population [32, 33]. Furthermore, this elevation in WBC counts was explained by increased neutrophil counts. Elevated rates of CV events were observed amongHIV+ heavy marijuana users beginning at relatively young ages (< 50 years), and were further increased in marijuana/tobacco co-users compared to users of only one substance. Further studies are needed to determine whether the effect of long-term heavy marijuana use on CV events is related to pro-inflammatory effects of non-tobacco smoke exposure, non-inflammatory effects (e.g., transient tachycardia and/or hypertension, elevated carboxyhemoglobin, hemodynamic effects, effects on platelets) [22-24], or a combination of these effects.
In healthy individuals, relatively few physical health outcomes have been clearly linked to marijuana use [4, 34-36]. However, adverse cardiovascular and cerebrovascular effects of recent marijuana use have been reported in some studies of the general population [4, 22-25]. The association between long-term heavy marijuana use and increased CV event rates has not been previously reported in HIV+ individuals. A study examining associations between substance use and coronary plaque measures in the MACS reported no strong effect of marijuana [20]. However, the study design was different from ours in several respects including the narrower definition of CV disease, and less stringent criteria for defining marijuana exposure. Furthermore, we excluded HCV+ subjects and other heavy illicit drug users from our study cohort. The association between marijuana use and CV events we detected was weaker than that of other known CV risk factors including age, cigarette smoking, and viral load > 400 copies/mL [14, 15, 17-19, 37]. In contrast to some prior studies [14, 15, 18, 19], we found weak or no significant associations between CV events and hypertension or cholesterol risk factors, which may reflect the younger age and high smoking prevalence in our study cohort.
The association we found between heavy marijuana use and elevated WBC has been reported in healthy young men [28], but to our knowledge has not previously been reported in HIV+ individuals. In line with previous studies of HIV-uninfected populations [28, 29, 32, 33], cigarette smoking was associated with elevated WBC count in our cohort of mostly middle-aged HIV+ men. The mechanism by which marijuana exposure increases WBC count remains poorly defined, but may be related to toxic or pro-inflammatory effects of smoke combustion products [36, 38].
The lack of association between marijuana use and HIV disease markers, progression to AIDS, mortality, or cancer reported here is consistent with prior observational [1, 3, 6, 8, 39] and case-control [5] studies. However, other studies reported associations between marijuana use and higher CD4 counts and/or lower viral load [9], higher CD4 counts [10], and slightly lower viral loads during the first year post-seroconversion [7]. While differences between these studies likely reflect differences in study populations, selection criteria, adjustment for confounders, and length of follow-up, the results reported here are consistent with other studies in MSM cohorts [1, 3, 6].
Strengths of this study include more selective inclusion and exclusion criteria compared to most previous studies: the chronic HIV cohort had controlled disease characteristics at baseline (CD4 count > 300 cells/μL, viral load ≤ 400 copies/mL), and subjects with heavy use of other illicit drugs and HCV co-infection were excluded. These factors have substantial effects on HIV disease markers and other outcomes, and therefore could confound efforts to detect effects of marijuana exposure. A further strength was the classification of long-term heavy marijuana use over years of follow-up, and strict criteria for classifying heavy and non-using subjects over this time span.
Limitations of this study include those inherent to studies of longitudinal cohorts, including the possibility that results may be specific to the MSM population recruited for the MACS, and non-random ascertainment and dropout biases. Available measures of marijuana exposure were self-reported frequency of use with no information regarding route of administration, source, quantity and potency. Based on available knowledge, the predominant mode of exposure was likely via marijuana smoking. These concerns are mitigated in part by the evaluation of two independent cohorts selected from differing calendar periods, which nonetheless show a consistent lack of association between marijuana use and HIV disease markers. Furthermore, we assessed cardiovascular events using time-updated data for marijuana and tobacco exposure during 10 years prior to endpoint.
In summary, we found no significant association between marijuana use and HIV disease progression or mortality. However, long-term heavy marijuana use was associated with increased midlife CV events in HIV+ men, independent of cigarette smoking and traditional risk factors. Furthermore, theincrease in CV events was additive in marijuana/tobacco co-users. These findings suggest that clinicians should consider heavy marijuana smoking as a modifiable risk factor when optimizing preventive care, particularly for individuals already at increased risk. In recent years, the prevalence of cigarette smoking has declined, while the prevalence of heavy marijuana use has remained high or increased in HIV-infected populations [3, 10, 40]. Given that traditional factors are not sufficient to explain elevated cardiovascular risk among HIV+ individuals [13, 15, 22], the identification of heavy marijuana smoking as a non-traditional risk factor helps to explain a portion of this elevated risk and warrants further investigation in other HIV-infected and uninfected populations.
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