In this first longitudinal study to our knowledge of marijuana smoking and risk of liver disease among HIV-HCV coinfected persons without significant fibrosis at baseline, we found no evidence that cannabis smoking increases the risk of progression to significant liver fibrosis or cirrhosis as measured by the standard APRI cutoffs. Furthermore, there was no evidence of any dose-response relationship with increasing cannabis use on APRI score. In addition, we did not observe any effect of marijuana use on the development of ESLD. We did observe a slight increase in the risk of progression to clinically diagnosed cirrhosis or cirrhosis and ESLD combined with high levels of marijuana smoking (33% or 13% increase for each additional 10 joints/week, respectively). However, this association disappeared after lagging the exposure, suggesting that previous cross-sectional studies reporting an association between marijuana smoking and liver fibrosis may be biased by reverse causation due to self-medication with marijuana for relief of symptoms related to significant liver fibrosis.
The 2 principal studies implicating marijuana as an independent risk factor for liver fibrosis were cross-sectional in design. Hézode et al [13
] estimated fibrosis progression rates among 270 HCV monoinfected patients undergoing biopsy in a single center, which were correlated with history of marijuana use obtained contemporaneously with performance of the liver biopsy. They found daily cannabis use was associated with values of fibrosis progression rates >0.074 Metavir U/yr and with severe fibrosis (≥F3), OR, 3.4 (1.5–7.4) and 2.3 (1.1–4.8), respectively. Ishida et al [15
] studied 204 consecutive HCV chronically infected patients recruited from community-based clinics who had undergone a liver biopsy; 21% were HIV coinfected. They found a strong association between daily cannabis use and moderate to severe fibrosis (OR, 6.78; 95% CI, 1.89–24.3) compared to mild fibrosis, but little association was apparent between cannabis use and the presence of mild fibrosis compared to no fibrosis. They concluded that cannabis may have little or no influence on the initiation of fibrosis, but once fibrosis is present, it may be an important cofactor in fibrosis progression.
To our knowledge, the only longitudinal study published described a small cohort of 58 HIV/AIDS patients recruited from an outpatient clinic and followed for 12 months and reported a non-statistically significant decrease in liver enzymes (ALT and AST) among dronabinol and/or marijuana users over the span of 1 year [16
]. Finally, Hézode et al [14
] estimated the association between cannabis use and the presence of marked steatosis (≥30% of hepatocytes containing cytoplasmic fat vacuoles) in a cross-sectional study of 315 HCV monoinfected patients undergoing biopsy. They found an OR of 0.5 (0.1–1.8) for occasional cannabis use and of 2.1 (1.01–4.5) for daily cannabis use compared no use.
Reported use for symptom relief was very prevalent suggesting that the association of daily cannabis use and more advanced fibrosis may, in fact, be related to an increased use for symptom management as disease advances. Interestingly, Ishida et al [15
] found that daily cannabis users had lower body mass index (BMI) and were much more likely to have medically prescribed cannabis (57% vs 9%), suggesting they may have been experiencing more symptoms.
The cannabinoid system consists of 2 receptors (CB1 and CB2) to which cannabinoids can bind [11
]. Depending on which receptor is expressed, cannabinoids could have opposite effects on the liver. Antifibrogenic and antiinflammatory effects of CB2 receptor have been observed in mice [10
]. Cannabinoids have been shown to decrease oxidative/nitrative stress and cell death [8
], normalize liver enzymes in mice [9
], and present antiinflammatory properties such as: (1) suppression of macrophage function, of antigen presentation and of chemokine production by human B cells; (2) inhibition of macrophage nitric oxide production, of cytotoxic T-cell activity and of T lymphocytes proliferative responses; and (3) regulation of tumor necrosis factor, interleukin-1, and interferon gamma production by human peripheral blood mononuclear cells [8
]. However, expression of the CB1 receptor seems to have pro-fibrogenic properties [10
]. In cell culture, cannabidiol induces death of hepatic stellate cells, activation of which contributes to development of fibrosis [7
]. The role of CB1/CB2 receptors expression and ratio is unclear in HCV progression. However, levels of CB1 are 6 times higher in chronic HCV patients than in controls, and twice higher in cirrhotic patients than in those at a low fibrosis stage [27
]. In this study, we selected a population with evidence of chronic HCV infection, thus more likely to express high levels of profibrogenic CB1 receptors. It is also possible that we favored the inclusion of those with higher CB2 expression by selecting a population free of significant fibrosis and ESLD. However, this is unlikely to have biased our results because we were interested in studying progression to liver disease.
Our study has several strengths. It is a large, prospective, cohort study that is broadly representative of HIV-HCV coinfected persons in care in Canada. In previous studies, patients were only selected based on having undergone liver biopsy, which potentially introduces selection bias. Indeed, excluded patients in the Ishida study were significantly less likely to use marijuana. We assessed marijuana use and other potential confounders such as alcohol use and HIV disease stage concurrently at each study visit and exposures were updated longitudinally, thus limiting the potential for reverse causality. In addition to using a noninvasive surrogate for significant fibrosis and cirrhosis, we corroborated our results with clinical outcomes.
There are several limitations worth noting. We used APRI as a noninvasive surrogate for significant liver fibrosis, which may underestimate the degree of fibrosis present and may be influenced by factors other than fibrosis that affect AST and platelet values. The area under the receiver operating characteristic (AUROC) curve of APRI is 0.77 for significant fibrosis and 0.83 for cirrhosis without significant change in accuracy in HIV-HCV coinfected as compared to HCV monoinfected patients [30
]. APRI is highly predictive of liver-related and all-cause mortality in HIV-HCV coinfection [19
]. However, the reference standard for the diagnosis of significant hepatic fibrosis, liver biopsy, is invasive, costly and prone to sampling error and therefore not amenable to be used repeatedly [33
]. Given the 18 years median duration of HCV infection, it is expected that many participants would have some degree of fibrosis at baseline. For this reason we also adjusted for baseline APRI in multivariate models, itself a strong predictor of liver fibrosis progression.
Although the relatively short follow-up time and the lack of information on duration of smoking before cohort entry do not allow us to make inference about long-term use of marijuana, the results of this study could still be valuable to clinicians who need to provide advice to their patients about immediate risks of marijuana smoking. Longer follow-up would be very valuable, however, to confirm our findings for extended exposure.
Clinical outcomes were relatively rare over the course of this study so it remains possible that we have missed a true effect (type II error) that may have been present if follow-up were extended so as to capture more events. However, the upper bounds of the 95% confidence intervals we observed are not consistent with an effect anywhere near as large as those previously reported (ORs of 3.4 and 6.78) –our study had 100% power to detect such a large effect for APRI ≥ 1.5 and APRI ≥ 2. Thus, if there is any effect of marijuana exposure it is likely to be quite small and only in more advanced disease. Indeed, our estimates are in line with lower bounds of the 95% confidence intervals reported from previous studies (ie, 1.01 and 1.89) and are much less than those for known important risk factors such as alcohol use.
We lacked detailed information on marijuana use history before cohort entry and therefore were only able to lag marijuana exposure by 6 months. However, in analyses when exposures were lagged by this amount, risks were attenuated. It is therefore unlikely that even more remote use would be expected to have had an effect. Moreover, exploratory analyses showed that current exposure provided the best fit to the data. We may have underestimated cannabis use as we did not collect information about ingested marijuana. We were also unable to investigate the effect of prescribed cannabinoid use such as marinol, nabilone, or sativex. However, use of these drugs was limited in our population.
It remains possible that the risk associated with cannabis exposure differs among HIV coinfected persons for whom there may be other more important predictors of liver disease. However, our analyses were controlled for antiretroviral use, and time updated CD4 cell count and HIV virologic control in addition to alcohol and drug use, which might be more common in our population. Finally, we could not assess the role of hepatic steatosis and insulin resistance, both important predictors of fibrosis progression [34
]. As marijuana use has been associated with the presence of steatosis, failure to account for steatosis would likely have biased our results away from the null rather than masking an effect of marijuana on fibrosis progression. Including BMI in the models did not change results (not shown).
To conclude, in this first prospective evaluation of liver disease progression among HIV-HCV infected persons, we could not demonstrate any important effect of marijuana on liver disease outcomes. A causal association is unlikely: hazard ratios were weak and most importantly were attenuated when accounting for temporality in the exposure-disease relationship and there was no dose-response relationship. It is likely that previous studies have been biased by reverse causality as patients use more marijuana to relieve symptoms as liver disease progresses.