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Introduction: Cannabis is widely used for recreational and medical purposes, but its therapeutic efficacy remains unresolved for many applications as data from retrospective studies show dramatic discrepancy. We hypothesized that false self-reporting of cannabis use and lack of differentiation of heavy users from light or occasional users contribute to the conflicting outcomes. Objective: The goal of this study was to develop an objective biomarker of cannabis use and test how application of such biomarker impacts clinical study outcomes and dose-response measures. Methods and Analysis: Population pharmacokinetic (PK) models of (-)-trans-Δ9-tetrahydrocannabinol (THC) and its metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC) were developed based on published studies reporting cannabinoid disposition in individual subjects following intravenous administration or smoking of cannabis. Plasma 11-COOH-THC concentration distributions in different cannabis user groups smoking cannabis were generated via Monte Carlo simulations, and plasma concentration cutoff values of 11-COOH-THC were developed to differentiate light and heavy daily cannabis users in clinical studies. The developed cutoff value was then applied to a retrospective study that assessed the impact of cannabis use on T cell activation in subjects with HIV who self-reported as either nonuser or daily user of cannabis. Results: The developed population PK models established plasma 11-COOH-THC concentration of 73.1 μg/L as a cutoff value to identify heavy daily users, with a positive predictive value of 80% in a mixed population of equal proportions of once daily and three times a day users. The stratification allowed detection of changes in T cell activation in heavy users which was not detected based on self-reporting or detectability of plasma cannabinoids. A proof-of-concept power analysis demonstrated that implementation of such cutoff value greatly increases study power and sensitivity to detect pharmacological effects of cannabis use. Conclusions: This study shows that the use of plasma 11-COOH-THC concentration cutoff value as an objective measure to classify cannabis use in target populations is critical for study sensitivity and specificity and provides much needed clarity for addressing dose-response relationships and therapeutic effects of cannabis.

Compared to young heterosexual men, young sexual and gender minorities (YSGM) have elevated systemic inflammation and unique intestinal microbial profiles, influenced by HIV infection and substance use. However, links between cannabis use and microbial dysbiosis in this population have not been well described. In this pilot study, we aimed to characterize the complex interrelationships between cannabis use and microbial community structure in YSGM in relationship to HIV status. Cannabis use was assessed by self-administered Cannabis Use Disorder Identification Test (CUDIT) questionnaires and rectal microbial community alpha-diversity metrics were assessed via 16S ribosomal ribonucleic acid (rRNA) sequencing in a subset of YSGM (n = 42) in the RADAR cohort (aged 16–29) in Chicago. Multivariable regression models were used to assess the relationship between cannabis use and microbiome alpha-diversity metrics, adjusting for HIV status and other risk characteristics, including inflammation, which was evaluated by plasma levels of C-reactive protein (CRP). Problematic cannabis use, but not general use, was significantly inversely associated with microbial community richness (Adj. Beta = −8.13; 95% confidence interval [CI]: −15.68 to −0.59) and Shannon diversity (Adj. Beta = −0.04; 95% CI: −0.07 to 0.009). No significant association was observed between CUDIT score and community evenness, nor was any significant moderation observed by HIV status. We observed that problematic cannabis use was associated with reduced microbial community richness and Shannon diversity, adjusting for within population differences in inflammation and HIV status. Future research should aim to assess how cannabis use contributes to microbiome-related health factors among YSGM and if decreasing cannabis use can restore gut microbial community structure. [ABSTRACT FROM AUTHOR]

Background Conflicting evidence exists on the impact of cannabis use on antiretroviral therapy (ART) adherence among people with human immunodeficiency virus (PWH). We leveraged data collected among older PWH to characterize longitudinal associations between cannabis use and ART adherence. Methods AIDS Clinical Trials Group (ACTG) A5322 study participants were categorized as <100% (≥1 missed dose in past 7 days) or 100% (no missed doses) ART adherent. Participants self-reported current (past month), intermittent (past year but not past month), and no cannabis (in past year) use at each study visit. Generalized linear models using generalized estimating equations were fit and inverse probability weighting was used to adjust for time-varying confounders and loss to follow-up. Results Among 1011 participants (median age, 51 years), 18% reported current, 6% intermittent, and 76% no cannabis use at baseline; 88% reported 100% ART adherence. Current cannabis users were more likely to be <100% adherent than nonusers (adjusted risk ratio [aRR], 1.53 [95% CI, 1.11–2.10]). There was no association between ART adherence and current versus intermittent (aRR, 1.39 [95% CI,.85–2.28]) or intermittent versus no cannabis use (aRR, 1.04 [95% CI,.62–1.73]). Conclusions Among a cohort of older PWH, current cannabis users had a higher risk of <100% ART adherence compared to nonusers. These findings have important clinical implications as suboptimal ART adherence is associated with ART drug resistance, virologic failure, and elevated risk for mortality. Further research is needed to elucidate the mechanisms by which cannabis use decreases ART adherence in older PWH and to advance the development of more efficacious methods to mitigate nonadherence in this vulnerable population. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) and malaria, caused by infection with Plasmodium spp., are endemic in similar geographical locations. As a result, there is high potential for HIV/ Plasmodium co-infection, which increases the pathology of both diseases. However, the immunological mechanisms underlying the exacerbated disease pathology observed in co-infected individuals are poorly understood. Moreover, there is limited data available on the impact of Plasmodium co-infection on antiretroviral (ART)-treated HIV infection. Here, we used the rhesus macaque (RM) model to conduct a pilot study to establish a model of Plasmodium fragile co-infection during ART-treated simian immunodeficiency virus (SIV) infection, and to begin to characterize the immunopathogenic effect of co-infection in the context of ART. We observed that P. fragile co-infection resulted in parasitemia and anemia, as well as persistently detectable viral loads (VLs) and decreased absolute CD4+ T-cell counts despite daily ART treatment. Notably, P. fragile co-infection was associated with increased levels of inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1). P. fragile co-infection was also associated with increased levels of neutrophil elastase, a plasma marker of neutrophil extracellular trap (NET) formation, but significant decreases in markers of neutrophil degranulation, potentially indicating a shift in the neutrophil functionality during co-infection. Finally, we characterized the levels of plasma markers of gastrointestinal (GI) barrier permeability and microbial translocation and observed significant correlations between indicators of GI dysfunction, clinical markers of SIV and Plasmodium infection, and neutrophil frequency and function. Taken together, these pilot data verify the utility of using the RM model to examine ART-treated SIV/ P. fragile co-infection, and indicate that neutrophil-driven inflammation and GI dysfunction may underlie heightened SIV/ P. fragile co-infection pathogenesis.