Reply to: Benefits of cannabis use for metabolic disorders and survival in people living with HIV with or without hepatitis C

We appreciate the interest shown by Santos et al.[1] regarding our editorial review. We agree with them that numerous observational studies point towards the beneficial effects of cannabis on hepatic fibrosis in persons living with HIV/hepatitis C virus (HCV). However, there are discrepancies in the findings between earlier cross-sectional observational studies [2–4] and later prospective longitudinal evaluations and a meta-analysis of liver disease progression among persons with HIV/HCV infection [5,6]. These later studies and meta-analysis suggest that cannabis use did not increase the prevalence or progression of hepatic fibrosis and, in fact, was associated with reduced prevalence of nonalcoholic fatty liver disease in cannabis users [5,6]. As suggested by Brunet et al.[5], earlier studies were biased by reverse causality, referring to the fact that patients modify their behaviour due to illness as the sicker, more symptomatic patients could be using more marijuana to relieve symptoms ad liver disease progresses. Difficulty in understanding whether cannabis has positive versus negative effects on different conditions likely relates to the fact that multiple factors affect the endocannabinoid system. Observational studies cannot control for all of these variables and multiple interactions between variables. Indeed, high-fat diet, alcohol intake and potentially obesity augment production of 2-arachidonoyl glycerol (2-AG) and arachidonyl ethanolamide which, in turn, activate CB1 and CB2 [7–9]. Furthermore, people with HIV and HIV/HCV on effective antiretroviral therapy have high rates of mood [10] and sleep disorders [11], neurocognitive aberrancies [12] and metabolic dysregulation [13], all of which are affected by the endocannabinoid system [14]. Therefore, it is plausible that the endocannabinoid system is dysregulated in people with HIV monoinfection and HIV/HCV coinfection, but this hypothesis has not yet been tested. Moreover, the impact of phytocannabinoids intake on the regulation of endocannabinoids during these infections remains unclear. Cannabinoid receptors are expressed on the gut epithelum. 2-AG, palmitoylethanolamide and N-arachidonoylethanolamine (anandamide) modulate epithelial barrier permeability and function, influencing microbial translocation into the bloodstream [15]. Given the central importance of gut dysfunctionality in HIV pathogenesis [16] and liver injury [17,18], one may hypothezie that the gut endocannabinoid system is disrupted in HIV and HIV/HCV infection. Altogether and going forward, efforts to better characterize the endocannabinoid system in health and in HIV and HIV/HCV infection, in addition to the effects of exogenous cannabinoid administration on the endocannabinoid system, are needed. Randomized controlled clinical trials, with biological specimens collected pre and post cannabinoid administration in clinically characterized human participants, will help us to understand the biology of the endocannabinoid system and pathways affected in gut-liver axis and in the context of hepatic fibrosis progression. These data will inform the design of therapeutic strategies to potentially slow or reverse the damage of HIV and HIV/HCV-associated liver disease and other comorbidities. Acknowledgements Conflicts of interest There are no conflicts of interest.

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