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Abstract

Cannabis use is frequent among people living with HIV and is associated with reduced systemic inflammation. We observed a faster HIV DNA decay during antiretroviral therapy among cannabis users, compared to no drug use. No cannabis-effect was observed on cellular HIV RNA transcription.
BRIEF REPORT
Clinical Infectious Diseases
BRIEFREPORT • CID 2019:XX (XX XXXX) • 1
Received 29 January 2019; editorial decision 29 April 2019; accepted 9 May 2019; published
online May 10, 2019.
Correspondence: S. Gianella, Division of Infectious Diseases, Department of Medicine,
University of California, San Diego, 9500 Gilman Drive, Stein Clinical Research Building #324,
La Jolla CA, 92093-0679 (gianella@ucsd.edu).
Clinical Infectious Diseases® 2019;XX(XX):1–4
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/ciz387
Eect of Cannabis Use on Human
Immunodeciency Virus DNA During
Suppressive Antiretroviral erapy
Antoine Chaillon,1 Masato Nakazawa,1 Christy Anderson,1 Aaron Christensen-Quick,1
RonaldJ. Ellis,2 Donald Franklin,2,3 SheldonR. Morris,1 and Sara Gianella1
1The Division of Infectious Diseases and Global Public Health, 2Department of Neurosciences,
and 3Department of Psychiatry, University of California, San Diego, La Jolla
Cannabis use is frequent among people living with human im-
munodeciency virus (HIV) and is associated with reduced
systemic inammation. We observed a faster HIV DNA decay
during antiretroviral therapy among cannabis users, compared
to those with no drug use. No cannabis eect was observed on
cellular HIV RNA transcription.
Keywords. MSM; cannabis; HIV DNA; cellular transcription.
Cannabis is widely consumed in the United States [1], particularly
among people living with human immunodeciency virus (HIV)
[2–4], and this has fostered an important debate regarding the
impact of cannabis on virologic and inammatory biomarkers.
On one hand, a recent study reported reduced adherence to anti-
retroviral therapy (ART) and retention in care in cannabis users
[5], and 2 other studies found no eects of cannabis on viral sup-
pression [4, 6]. On the other hand, 1 study has demonstrated ben-
ecial impacts of cannabis on plasma HIV RNA among recently
infected people living with HIV (PLWH) [7]. More recently,
Manuzak etal [8] evaluated the impact of cannabis use on in-
ammation and immune activation in ART-treated PLWH and
reported that cannabis use was associated with (1) reduced acti-
vation of CD4+ and CD8+ T cells and (2) a shi in the composi-
tion of the monocyte populations in peripheralblood.
Here, we investigated the eect of cannabis use (with or
without other drugs) on the decay and transcriptional activity
of the HIV reservoir during suppressiveART.
METHODS
Ethics Statement
The study was approved by the University of California
San Diego Human Research Protections Program. All adult
participants provided written informed consent.
Study Cohort and ClinicalData
There were 48 men who have sex with men (MSM) coenrolled
in the San Diego Primary Infection Resource Consortium
[9] and in the Translational Methamphetamine Acquired
Immunodeficiency Syndrome (AIDS) Research Center cohort
[10]. The estimated duration of infection (EDI) was determined
using serologic and virologic parameters [9]. Amedian of 4
(interquartile range [IQR] 1–5) longitudinal peripheral blood
mononuclear cells (PBMCs) and plasma samples per individual
were collected over a median of 22months (IQR 12–31) fol-
lowing ART initiation. Absolute CD4+ and CD8+ T cell counts,
plasma HIV RNA levels (Amplicor, Roche), and self-reported
ART adherence were measured.
To ascertain substance use (not including alcohol), we
utilized 3 validated questionnaires, including the World Health
Organization Composite International Diagnostic Interview–
Substance Abuse Module 2.1 [10, 11, 12]. We were primarily
interested in the eect of cannabis on cellular HIV DNA and
HIV RNA. Due to the small sample size and to reduce the false
discovery rate, we combined all other drugs (except cannabis).
is yielded 4 groups, based on self-reported drug use: (1) no
drug use; (2) cannabis use only; (3) use of drugs other than can-
nabis (“other drugs”); and (4) use of both cannabis and other
drugs (“both drugs”).
Total Cellular Human Immunodeficiency Virus DNA andRNA
DNA was extracted from 5 million PBMCs for each time point
using an AllPrep DNA/RNA Mini Kit (Qiagen, CA). Total HIV
DNA (polymerase) was quantified by droplet digital polymerase
chain reaction and normalized to the housekeeping gene ribo-
nuclease P/MRP Subunit P30 [13]. Levels of all fully elongated
and correctly processed HIV mRNA molecules were quantified
[14] and normalized to total RNA concentration [15].
Flow Cytometry
Markers of T cell activation (CD38+HLA-DR+) and monocyte
activation (CD16+) were assessed by flow cytometry [16].
Statistical Analyses
We developed (generalized) linear mixed-effects regression
models to investigate the relationship of cannabis and other
drugs on 2 outcomes during ART: (1) changes in HIV DNA
levels, and (2) cell-associated HIV RNA transcripts (detectable
or undetectable). For each model, we included a random inter-
cept for subject and the following fixed effects: (1) time from
ART initiation (ie, slope); (2) drug use; and (3) time by drug use
(ie, the difference in slopes). To determine which fixed effects
to include in the final model, we tested whether the outcome
changed over time among all participants. If it did change at
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2 • CID 2019:XX (XX XXXX) • BRIEF REPORT
the 10% significance level, we subsequently tested whether
the drug user groups differed in the rate of change and in the
outcome level at ART initiation; if not, we tested whether the
groups differed in the overall outcome level. To control for
other sources of variability, we added relevant covariates (ie,
age, time from EDI to ART, CD4 count, CD4/CD8 ratio, mean
% activated [CD38+HLA-DR+] of CD4+ and CD8+ T cells, and
mean % of CD14+CD16+ monocytes), if associated with the out-
come at P<.10 in individual models. Our final models include
all predictors and covariates that were significant at P < .05.
Because 34% of all time points exhibited levels of cellular HIV
RNA below the limits of detection, we used mixed-effects lo-
gistic regression to analyze this outcome. Data are expressed as
median (IQR).
RESULTS
Study Cohort and Samples
This study evaluated 206 blood samples from 48 MSM who
initiated ART within a median of 4months (IQR 1–6) from
EDI and achieved suppressed HIV RNA within a median of
5 months (IQR 3–8), without any documented blips of HIV
RNA replication. Of the 48 individuals, 10 (21%) reported
no drug use, 5 (11%) reported use of cannabis only, 16 (33%)
reported use of drugs other than cannabis, and 17 (35%) re-
ported use of cannabis and other drugs. Summaries of cohort
characteristics and drug self-reports at ART initiation are pro-
vided in Supplementary Tables 1 and 2.
Predictors of Human Immunodeficiency Virus DNA Levels andDecay
The median unadjusted HIV DNA level at ART initiation was
2.4 log10 copies/106 cells (IQR 1.0–3.1) with a significant de-
crease of HIV DNA over time among all participants (P<.01;
Supplementary Table 3). Cannabis-only users had signifi-
cantly greater HIV DNA levels at the time of ART initiation
(P=.04), but subsequently experienced a faster HIV DNA decay,
compared to participants with no drug use (P <.01; Figure 1).
Participants who used other drugs (with or without cannabis)
had similar levels of HIV DNA at ART initiation (P= .41 and
P=.66, respectively) and during ART (P=.43 and P=.76, re-
spectively), compared to those who used no drugs. The 4 groups
did not differ in baseline CD4 counts (P=.80) or EDIs (P=.46).
Regarding markers of cellular activation, study participants
taking other drugs had a persistent, higher proportion of ac-
tivated (CD38+HLA-DR+) CD8+ T cells, as compared to
those who used no drugs, even aer controlling for signi-
cant covariates. ere were no dierences by groups related
to CD38+HLA-DR+CD4+ T cells or CD14+CD16+ monocytes.
Overall, the mean percentage of CD38+HLA-DR+CD8+ T cells
was positively associated with HIV DNA levels in the individual
model (P<.02), but this was no longer signicant when drug
groups were included (P=.08).
*
No Drug Cannabis Only Other Drugs Both Drugs
01234012340123401234
0
1
2
3
4
Time (Ln Month Since ART Initiation)
HIV DNA
(
log10 copies 10
6
CD4
)
Figure 1. Observed HIV DNA (log10 copies/106 CD4+) in cohort during ART as a function of time (Ln months since ART Initiation) and drug use. The thin lines and dots
indicate individual data points. Thick lines and shaded areas indicate model-estimated values and their 95% confidence intervals. *P<.05: the mean HIV DNA level at ART
initiation and slope differences compared to the no-drug group. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus;Ln, natural log.
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BRIEFREPORT • CID 2019:XX (XX XXXX) • 3
Cellular Human Immunodeficiency Virus RNA Transcription
The median levels of cellular HIV RNA at baseline were 4.9 log10
copies/ml (IQR 3.8–5.7; Supplementary Table 1), and all of the
participants had detectable levels at ART initiation. Participants
who reported use of cannabis (with or without other drugs),
did not exhibit significantly different proportions of detectable
cellular HIV RNA (P=.59 and P=.28, respectively). However,
participants who used other drugs were significantly more
likely to have detectable cellular HIV RNA levels during ART
(P = .01). Similarly, participants with higher peak HIV RNA
levels (before ART initiation) and higher mean percentages of
activated CD8+ T cells had more detectable cellular HIV RNA
levels during ART (P<.05). Participants with higher CD4/CD8
ratios had less detectable cellular HIV RNA levels (P < .10).
Interestingly, only the other drug effect remained significant for
cellular HIV RNA when included in a final multivariate model
(P=.01; other effects, P>.4; Supplementary Table 4).
DISCUSSION
In this longitudinal study of PLWH with well-characterized histories
of substance use, we found that exclusive use of cannabis was as-
sociated with a faster decay of HIV DNA, but had no impact on
cell-associated HIV RNA transcription or cellular activation during
suppressive ART. However, the consumption of other drugs was as-
sociated with increased CD8+ T cell activation and with increased
cellular HIV RNA transcription during ART. Our results are con-
sistent with a previous study reporting that cannabis use was asso-
ciated with lower plasma HIV RNA levels among recently infected
PLWH [7], and with reports of reduced HIV replication and cel-
lular infection rates in the presence of cannabinoids in vitro [17, 18].
Further, cannabis use has been previouslyassociated with decreased
frequencies of interleukin 23 and tumor necrosis factor α [8] and,
more recently, with the reduction of interferon-γ inducible protein
10 levels in plasma [19]. Altogether, these publishedfindings point
to a potential anti-inflammatory effect of cannabis that, in turn,
might positively impact HIV replication and persistence [20], al-
though another study has suggested that tetrahydrocannabinol may
enhance HIV replication by suppressing immune functions in mice
[21], and this possibility should be evaluated in future, larger clin-
ical studies. In our study, the effect of cannabis on HIV DNA was
not evident when cannabis was used in combination with any other
drugs, highlighting the complex interplay between drug use and
viral infections.
e small sample size and the multiple potential confounding
factors among participants with a complex history of drug use
are major limitations to this report. Furthermore, cannabis
use was not conrmed by the direct measurement of cannabis
metabolites, and only relied on self-report. While inaccurate
self-reporting could confound our observations, studies have
demonstrated the reliability of self-reported drug use [22].
e mechanisms by which cannabis impacts the HIV res-
ervoir—whether directly or indirectly by limiting immune
activation, the infection of CD4+ T cells, and macrophages and
inammation—remain uncertain. Further work is necessary
to explore these mechanisms and the interactions with other
drugs, which have been associated with contradictory eects on
the immune system. ese ndings may have implications for
and rearm the need for regular screening for substance use
in HIV care settings and for a holistic approach to HIV cures
from healthcare providers, physicians, epidemiologists, and
researchers.
SupplementaryData
Supplementary materials are available at Clinical Infectious Diseases on-
line. Consisting of data provided by the authors to benet the reader, the
posted materials are not copyedited and are the sole responsibility of the
authors, so questions or comments should be addressed to the corre-
sponding author.
Notes
Financial support. is work was supported by the National Institute on
Drug Abuse (grant number P50 DA026306).
Potential conicts of interest. A. C. has received funding from the
National Institutes of Health (grant number R21 AI131971-01) and the
University of San Diego Center for Acquired Immunodeciency Syndrome
Research, a National Institutes of Health–funded program (grant number
P30 AI036214). S.G. has received funding from the National Institutes of
Health (grant numbers HD094646, AI027763, AI134295, and AI68636).
R.J. E.has received funding from the National Institutes of Health (grant
numbers R01 AG048650, P30 MH62512, and R01 MH107345). S.R. M.has
received grants from Gilead Sciences and California HIV/AIDS Research
Program and other support from Bristol Myers Squibb, Forty Seven Inc.,
and Impact Biomedicines (now Celgene), outside the submitted work. All
other authors report no potential conicts. All authors have submitted the
ICMJE Form for Disclosure of Potential Conicts of Interest. Conicts that
the editors consider relevant to the content of the manuscript have been
disclosed.
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... We analyzed HIV DNA in blood as a marker of reservoir size in men who had sex with men and initiated ART within a median of 4 months of estimated date of HIV infection. All achieved suppressed HIV RNA within a median of 5 months [93]. Exclusive use of cannabis, as compared to no substance use or use of other drugs, was associated with a faster decay of HIV DNA during suppressive ART. ...
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Objective: Cognitive deficits and microstructural brain abnormalities are well documented in HIV-positive individuals (HIV+). This study evaluated whether chronic marijuana (MJ) use contributes to additional cognitive deficits or brain microstructural abnormalities that may reflect neuroinflammation or neuronal injury in HIV+. Method: Using a 2 × 2 design, 44 HIV+ participants [23 minimal/no MJ users (HIV+), 21 chronic active MJ users (HIV + MJ)] were compared to 46 seronegative participants [24 minimal/no MJ users (SN) and 22 chronic MJ users (SN + MJ)] on neuropsychological performance (7 cognitive domains) and diffusion tensor imaging metrics, using an automated atlas to assess fractional anisotropy (FA), axial (AD), radial (RD), and mean (MD) diffusivities, in 18 cortical and 4 subcortical brain regions. Results: Compared to SN and regardless of MJ use, the HIV+ group had lower FA and higher diffusivities in multiple white matter and subcortical structures (p < 0.001-0.050), as well as poorer cognition in Fluency (p = 0.039), Attention/Working Memory (p = 0.009), Learning (p = 0.014), and Memory (p = 0.028). Regardless of HIV serostatus, MJ users had lower AD in uncinate fasciculus (p = 0.024) but similar cognition as nonusers. HIV serostatus and MJ use showed an interactive effect on mean diffusivity in the right globus pallidus but not on cognitive function. Furthermore, lower FA in left anterior internal capsule predicted poorer Fluency across all participants and worse Attention/Working Memory in all except SN subjects, while higher diffusivities in several white matter tracts also predicted lower cognitive domain Z-scores. Lastly, MJ users with or without HIV infection showed greater than normal age-dependent FA declines in superior longitudinal fasciculus, external capsule, and globus pallidus. Conclusions: Our findings suggest that, except in the globus pallidus, chronic MJ use had no additional negative influence on brain microstructure or neurocognitive deficits in HIV+ individuals. However, lower AD in the uncinate fasciculus of MJ users suggests axonal loss in this white matter tract that connects to cannabinoid receptor rich brain regions that are involved in verbal memory and emotion. Furthermore, the greater than normal age-dependent FA declines in the white matter tracts and globus pallidus in MJ users suggest that older chronic MJ users may eventually have lesser neuronal integrity in these brain regions.
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Objective To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma. Methods We measured a panel of proinflammatory cytokines (interleukin [IL]-16, C-reactive protein [CRP], IL-6, interferon gamma-induced protein [IP]-10, soluble CD14, and soluble tumor necrosis factor receptor type II [sTNFRII]) in CSF and blood plasma in PWH and HIV− individuals who did or did not use cannabis at various levels of exposure. Participants in this observational cohort were recruited from community sources and underwent lumbar puncture and phlebotomy. Cannabis use parameters were characterized by self-report based on a semistructured timeline follow-back interview. Cytokines were measured using commercially available immunoassays. Data were analyzed using factor analysis. Results Participants were 35 PWH and 21 HIV− individuals, mean (SD) age 45.4 (14.5) years, 41 cannabis ever users, and 15 never users. PWH and HIV− were not different in recency, cumulative months, grams, or density of cannabis use. A factor analysis using CSF biomarkers yielded a factor loading on CRP, IL-16, and sTNFRII that was significantly associated with recency of cannabis use (more recent use associated with lower factor 1 values, reflecting less inflammation; r = 0.331 [95% CI 0.0175, 0.586]). In particular, more recent cannabis use was related to lower IL-16 levels (r = 0.549 [0.282, 0.737]). Plasma biomarkers yielded a factor loading on sTNFRII and IP-10 that was associated with more recent cannabis use (more recent use related to less inflammation; r = 0.374 [0.0660, 0.617]). Conclusions Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns. These results are consistent with compartmentalization of immune effects of cannabis. The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction.
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Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4 ⁺ T cell activation was higher and CD8 ⁺ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4 ⁺ T cells are more vulnerable to HIV infection, while the loss of CD8 ⁺ T cell degranulation may impede the proper killing of infected cells.
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Background: Cannabis is a widely used drug in the United States, and the frequency of cannabis use in the human immunodeficiency virus (HIV)-infected population is disproportionately high. Previous human and macaque studies suggest that cannabis may have an impact on plasma viral load; however, the relationship between cannabis use and HIV-associated systemic inflammation and immune activation has not been well defined. Methods: The impact of cannabis use on peripheral immune cell frequency, activation, and function was assessed in 198 HIV-infected, antiretroviral-treated individuals by flow cytometry. Individuals were categorized into heavy, medium, or occasional cannabis users or noncannabis users based on the amount of the cannabis metabolite 11-nor-carboxy-tetrahydrocannabinol (THC-COOH) detected in plasma by mass spectrometry. Results: Heavy cannabis users had decreased frequencies of human leukocyte antigen (HLA)-DR+CD38+CD4+ and CD8+ T-cell frequencies, compared to frequencies of these cells in non-cannabis-using individuals. Heavy cannabis users had decreased frequencies of intermediate and nonclassical monocyte subsets, as well as decreased frequencies of interleukin 23- and tumor necrosis factor-α-producing antigen-presenting cells. Conclusions: While the clinical implications are unclear, our findings suggest that cannabis use is associated with a potentially beneficial reduction in systemic inflammation and immune activation in the context of antiretroviral-treated HIV infection.
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Objective: Chronic immune activation and elevated numbers of circulating activated monocytes (CD16) are implicated in HIV-associated neuroinflammation. The objective was to compare the level of circulating CD16 monocytes and interferon-γ-inducible protein 10 (IP-10) between HIV-infected cannabis users (HIV+MJ+) and non-cannabis users (HIV+MJ-), and determine whether in vitro Δ-Tetrahydrocannabinol (THC), a constituent of cannabis, affected CD16 expression as well as IP-10 production by monocytes. Design: The levels of circulating CD16 monocytes and IP-10 from HIV+MJ- and HIV+MJ+ donors were examined. In vitro experimentation using THC was performed on primary leukocytes isolated from HIV-MJ-, HIV+MJ- and HIV+MJ+ donors to determine if THC has an impact on CD16 monocyte and IP-10 levels. Methods: Flow cytometry was used to measure the number of blood CD16 monocytes and serum IP-10 from HIV+MJ- and HIV+MJ+ donors. Peripheral blood mononuclear cells (PBMC) were isolated from HIV-MJ- and HIV+ (MJ- and MJ+) donors for in vitro THC and IFNα treatment, and CD16 monocytes and supernatant IP-10 were quantified. Results: HIV+MJ+ donors possessed a lower level of circulating CD16 monocytes and serum IP-10, compared to HIV+MJ- donors. Further, monocytes from HIV+MJ+ donors were unable to induce CD16 expression when treated with in vitro IFNα, while HIV-MJ- and HIV+MJ- donors displayed pronounced CD16 induction, suggesting anti-inflammatory effects by cannabis. Lastly, in vitro THC treatment impaired CD16 monocyte transition to CD16 and monocyte-derived IP-10. Conclusions: Components of cannabis, including THC, may decelerate peripheral monocyte processes that are implicated in HIV-associated neuroinflammation.
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We assessed the association between marijuana use and retention in HIV care through a retrospective cohort study of patients engaged in care at a large HIV clinic in 2011 and 2012. Two different retention outcomes were assessed: not meeting the Institute of Medicine’s (IOM) retention definition (≥2 provider visits ≥90 days apart in a calendar year) and no-show visits. Any marijuana use and frequency of marijuana use were obtained from a substance use screening questionnaire administered at each clinic visit. Modified Poisson regression was used to estimate risk ratios and 95% confidence intervals for the association between marijuana use and retention outcomes. Marijuana use was reported by 17% of 1791 patients and 21% were not retained (IOM definition). Marijuana use was not associated with the IOM retention outcome, but was associated with missing the next scheduled appointment. A non-linear dose–response was observed for frequency of marijuana use and missed visits, with daily users having the highest risk compared to non-users. Daily marijuana use had a negative impact on HIV clinic attendance. Further research is needed to elucidate the mechanisms by which marijuana use affects this outcome to inform targeted interventions.
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Introduction and AimsCannabis use is common among people who are living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). While there is growing pre-clinical evidence of the immunomodulatory and anti-viral effects of cannabinoids, their possible effects on HIV disease parameters in humans are largely unknown. Thus, we sought to investigate the possible effects of cannabis use on plasma HIV-1 RNA viral loads (pVLs) among recently seroconverted illicit drug users. Design and Methods We used data from two linked longitudinal observational cohorts of people who use injection drugs. Using multivariable linear mixed-effects modelling, we analysed the relationship between pVL and high-intensity cannabis use among participants who seroconverted following recruitment. ResultsBetween May 1996 and March 2012, 88 individuals seroconverted after recruitment and were included in these analyses. Median pVL in the first 365 days among all seroconverters was 4.66 log10cmL(-1). In a multivariable model, at least daily cannabis use was associated with 0.51 log10cmL(-1) lower pVL (=-0.51, standard error=0.170, P value=0.003). Discussion and Conclusions Consistent with the findings from recent in vitro and in vivo studies, including one conducted among lentiviral-infected primates, we observed a strong association between cannabis use and lower pVL following seroconversion among illicit drug-using participants. Our findings support the further investigation of the immunomodulatory or antiviral effects of cannabinoids among individuals living with HIV/AIDS. [Milloy M-J, Marshall B, Kerr T, Richardson L, Hogg R, Guillemi S, Montaner JSG, Wood E. High-intensity cannabis use associated with lower plasma human immunodeficiency virus-1 RNA viral load among recently infected people who use injection drugs. Drug Alcohol Rev 2015;34:135-40]
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Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4+ T cells in blood (P<0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4+ T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P=0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (P=0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4+ (P<0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these described associations.
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Significant changes have taken place in the policy landscape surrounding cannabis legalization, production, and use. During the past 20 years, 25 states and the District of Columbia have legalized cannabis and/or cannabidiol (a component of cannabis) for medical conditions or retail sales at the state level and 4 states have legalized both the medical and recreational use of cannabis. These landmark changes in policy have impacted cannabis use patterns and perceived levels of risk. However, despite this changing landscape, evidence regarding the short- and long-term health effects of cannabis use remains elusive. While a myriad of studies have examined cannabis use in all its various forms, often these research conclusions are not appropriately synthesized, translated for, or communicated to policy makers, health care providers, state health officials, or other stakeholders who have been charged with influencing and enacting policies, procedures, and laws related to cannabis use. Unlike other controlled substances such as alcohol or tobacco, no accepted standards for safe use or appropriate dose are available to help guide individuals as they make choices regarding the issues of if, when, where, and how to use cannabis safely and, in regard to therapeutic uses, effectively. Shifting public sentiment, conflicting and impeded scientific research, and legislative battles have fueled the debate about what, if any, harms or benefits can be attributed to the use of cannabis or its derivatives, and this lack of aggregated knowledge has broad public health implications. The Health Effects of Cannabis and Cannabinoids provides a comprehensive review of scientific evidence related to the health effects and potential therapeutic benefits of cannabis. This report provides a research agenda—outlining gaps in current knowledge and opportunities for providing additional insight into these issues—that summarizes and prioritizes pressing research needs.
Article
Background: Reforms to the legal status of medical and non-medical cannabis are underway in many jurisdictions, including Canada, as are renewed efforts to scale-up HIV treatment-as-prevention (TasP) initiatives. It has been suggested that high-intensity cannabis use may be associated with sub-optimal HIV treatment outcomes. Thus, using data from a setting with a community-wide treatment-as-prevention (TasP) initiative coinciding with increasing access to medical cannabis, we sought to investigate the possible impact of high-intensity cannabis use on HIV clinical outcomes. Methods: Data was derived from the ACCESS study, a prospective cohort of HIV-positive people who use illicit drugs (PWUD) in Vancouver, Canada. Cohort data was confidentially linked to comprehensive clinical profiles, including records of all antiretroviral therapy (ART) dispensations and longitudinal plasma HIV-1 RNA viral load (VL) monitoring. We used generalized estimating equations (GEEs) to estimate the longitudinal bivariable and multivariable relationships between at least daily cannabis use and two key clinical outcomes: overall engagement in ART care, and achieving a non-detectable VL among ART-exposed participants. Results: Between December 2005 and June 2015, 874 HIV-positive PWUD (304 [35%] non-male) were included in this study. In total, 788 (90%) were engaged in HIV care at least once over the study period, of whom 670 (85%) achieved non-detectable VL at least once. In multivariable analyses, ≥ daily cannabis use did not predict lower odds of ART care (Adjusted Odds Ratio [AOR]: 1.02, 95% confidence interval [CI]: 0.77-1.36) or VL non-detectability among ART-exposed (AOR: 0.96, 95% CI: 0.75-1.21). Upon testing for potential interactions, ≥ daily cannabis use was found to be negatively associated with ART engagement during periods of binge alcohol use (p<0.05). Conclusion: With the exception of frequent cannabis use during periods of binge alcohol use, our results showed no statistically significant impact of daily cannabis use on the likelihood of ART care or VL non-detectability among ART-exposed HIV-positive PWUD. These findings are reassuring in light of the impending legalization of cannabis in Canada and ongoing efforts to expand TasP initiatives.
Article
Background: Marijuana use is common among persons living with HIV (PLWH), but studies on its effect on HIV clinical outcomes are limited. Objectives: We determined the association between marijuana use and HIV viral suppression among PLWH. Methods: Data came from five repeated cross-sections (2009-2013) of the Florida Medical Monitoring Project, a population-based sample of PLWH in Florida. Data were obtained via interview and medical record abstraction (MRA). Weighted logistic regression models were used to determine the association between marijuana use (past 12 months) and durable viral suppression (HIV-1 RNA value of ≤ 200 copies/milliliter in all measurements within the past 12 months). Results: Of the 1,902 PLWH receiving antiretroviral therapy, completed an interview, and had a linked MRA, 20% reported marijuana use (13% less than daily and 7% daily use) and 73% achieved durable viral suppression. In multivariable analysis, marijuana use was not significantly associated with durable viral suppression in daily [Adjusted Odds Ratio (AOR): 0.87, 95% confidence interval (CI): 0.58, 1.33] or in less than daily [AOR: 0.83, 95% CI: 0.51, 1.37] users as compared to non-users when adjusting for sociodemographic factors, time since HIV diagnosis, depressive symptoms, alcohol, cigarette and other substance use. Conclusion: In this sample of PLWH receiving medical care in Florida, there was no statistically significant association between marijuana use and viral suppression. However, as the limits of the confidence intervals include effects that may be considered to be clinically important, there is a need for additional evidence from other samples and settings that include more marijuana users.
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This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of ∆(9)-THC extracted from the marijuana plant, and synthetic cannabinoids. Of particular interest are synthetic compounds that are CB2 receptor (CB2R) selective agonists. As the CB2R is principally expressed on cells of the immune system, agonists that target this receptor, and not CB1 (which is mainly expressed on neurons), have the possibility of altering immune function without psychoactive effects. The overall conclusion of the studies discussed in this review is that cannabinoids that bind to the CB2 receptor, including ∆(9)-THC and CB2 selective agonists are immunosuppressive. The studies provide objective evidence for potentially beneficial effects of marijuana and ∆(9)-THC on the immune system in conditions where it is desirable to dampen immune responses. Evidence is also reviewed supporting the conclusion that these same compounds can sensitize to some infections through their immunosuppressive activities, but not to others. An emerging area of investigation that is reviewed is evidence to support the conclusion that CB2 selective agonists are a new class of immunosuppressive and anti-inflammatory compounds that may have exceptional beneficial effects in a variety of conditions, such as autoimmune diseases and graft rejection, where it is desirable to dampen the immune response without psychoactive effects.