Marijuana and the Liver. Lauren Myers MMsc, PA-C

Transcription

1 Marijuana and the Liver Lauren Myers MMsc, PA-C

2 Disclosures 1. The speaker/planner Lauren Myers, MMSc, PA-C have no relevant financial relationships to disclose. 2. The planners, Atif Zaman, MD, MPH have no relevant financial relationships to disclose.

3 Marijuana use in Oregon?

4 Oregon Ballot Measure 91 Effective July 1, 2015 Passage legalized the recreational use of marijuana, based on regulation and taxation to be determined by the Oregon Liquor Control Commission Legalizes the possession of use of marijuana adults 21+ Carry up to 1(one) ounce of marijuana, keep up to 8 ounces at home per household and grow up to 4 plants

5 Demographics of Marijuana users in Oregon Oregon marijuana use exceeds national trends Consistently higher in young adults (18-25) compared to older adults (26 years or older) Marijuana use in those 26 years and older has approximately doubled since % of adults reported current medical marijuana use Medical marijuana use increases with age (25-64) Oregon Public Health Division. Marijuana report: Marijuana use, attitudes and health effects in Oregon, OHA 2016

6 Current marijuana use among Oregon and US Oregon Public Health Division. Marijuana report: Marijuana use, attitudes and health effects in Oregon, OHA 2016

7 Oregon Medical Marijuana Program (OMMP) Attending Physician (MD or DO) may recommend use of medical marijuana for following medical conditions: Cancer Glaucoma Degenerative or pervasive neurologic condition HIV/AIDS Post-Traumatic stress Disorder A medical condition or treatment for medical condition that produces: Cachexia Severe pain Severe nausea Seizures Persistent muscle spasm

8 Oregon medical marijuana patient conditions 2015

9 Cannabis Nearly 500 different chemical compounds isolated from Cannabis 2 main species of Cannabis plant Cannabis sativa Cannabis indica Most clinically relevant are phytocannabinoids concentrated in plant s flowering buds Δ9 tetrahydrocannabinol (THC)- psychoactive effects ~70 phytocannabinoids including cannabidiol (CBD) Gerich et al, Am J Gastro, 2015, Atakan, Ther Adv Psychopharmacol, 2012

10 Endocannabinoid system Phytocannabinoids signal through endogenous cannabinoid system G-protein coupled cannabinoid receptors CB 1- central and peripheral neurons, colonic epithelium CB 2- immune cells Expression of cannabinoid receptors limited in the normal liver but increased in experimental liver injury/cirrhosis Up-regulation of non-parenchymal cells along fibrous septae CB2 receptors in inflammatory cells/bile ducts, epithelial cells, and hepatocytes with non-alcoholic steatosis/steatohepatitis CB1/CB2 pro-fibrogenic and anti-fibrogenic effects in the liver Izzo, et al, Gut, 2008

11 Cannabis Effects on the Liver?

12 Cannabis Use and the Severity of Fibrosis in HCV Prospective cohort, n=204 Cannabis use reported within last 12 months Daily (13.7%) Occasional (45.1%) Never (41.2%) Daily cannabis use independent risk factor for moderate to severe fibrosis (OR, 6.78; 95% CI, , P=.003) Daily cannabis users 7-fold higher odds of moderate to severe fibrosis compared to non-daily users Little association apparent between daily users and presence mild fibrosis compared with no fibrosis Ishida et al, Clin Gastro and Hep. 2008

13 Daily Cannabis associated with Fibrosis Progression in Active HCV N=279, known exposure length of HCV Smoking cannabis Daily users (33%) Occasional users (14.8%) Non-users (52.2%) Daily cannabis independent predictor of rapid fibrosis progression rate (OR = 3.6 [ ]) Severe Fibrosis ( F3) predicted by daily cannabis use (OR= 2.5 [ ]) Hézode, et al. Hepatology. 2005

14 Daily Cannabis as a Risk Factor for Steatosis in Active HCV N= 315 undergoing routine biopsy with untreated HCV 24.1% Daily cannabis users Marked Steatosis defined 30% on biopsy Marked steatosis more frequent in daily cannabis users (after adjustment for HCV GT, alcohol intake) Hézode et al, Gastroenterology. 2008

15 Marijuana Smoking Not Associated with Progression of Liver disease in HIV-HCV Coinfection Prospective multicenter cohort of HIV/HCV Co-infected individuals (followed median 31.8 months), no significant fibrosis, N=690 53% smoked marijuana in past 6 months (median 7 joints/week), 40% smoked daily Clinical end point progression of APRI 1.5, Cirrhosis (APRI 2, radiologic findings cirrhosis), or ESLD Statistical analysis of marijuana exposures 6-12 months before outcome assessment to reduce reverse causation bias Marijuana smoking associated with slightly increased risk of progression to cirrhosis/esld but no longer significant when exposure was lagged (HR 1.10; 95% CI ) Brunet et al. Clin Infec Diseases. 2013

16 Cannabinoids and Other Liver Diseases Δ9 tetrahydrocannabinol (ie THC) and JWH-015 (CB2 agonist) reduced viability of human hepatocellular carcinoma cell lines in mice models¹ Δ9-THC and JWH-015 inhibited tumor growth and ascites in mice models Dronabinol (oral form of Δ9-THC) decreased pruritus, improved sleep in case studies of cholestatic liver disease with intractable pruritus² Vara et al. Cell Death and Differentiation Neff et al. Am J of Gastroenterology. 2002

17 Improving liver fibrosis by blocking CB 1 cannabinoid receptor Activation of CB 1 receptors promotes progression fibrosis CB 1 receptor is highly induced in human cirrhosis and liver fibrogenic cells Treatment with CB 1 antagonist SR141716A inhibited fibrosis progression in mice models of chronic liver injury Genetic and pharmacologic inactivation CB 1 receptors: Decreased fibrogenesis via decreasing hepatic transforming growth factor (TGF)-ββ1 Decreased accumulation fibrogenic cells in the liver, growth inhibition of hepatic myofibroblasts Teixeira-Clerc et al. Nature Medicine. 2006

18 Cannabis Use and HCV Treatment?

19 Cannabis use and IFN/RBV treatment N= 71, 31% cannabis users 17 of 71 discontinued therapy early (24%), 1 cannabis user (p=0.01) 30% (21/71) achieved SVR 54% cannabis users achieved SVR vs 18% non-users (p=0.009) Cannabis users were equally likely to take >80% of HCV meds Cannabis users were more likely to remain on treatment for >80% of projected duration (p=0.01) Sylvestre et al. Eur J Gastroenterol Hepatol. 2006

20 High Adherence to DAA Therapy in Inner-City Patient Population N=60, mono-infected, treatment naïve 17% had used marijuana within 6 months of study medications Enrolled into 3 study arms: LDV/SOF 12 weeks LDV/SOF+ GS-9451 (2 pills) 6 weeks LDV/SOF+GS-9669 (3 pills, two in AM, one in PM) for 6 weeks In 12 week arm, lower adherence among participants who used drugs (marijuana, cocaine or heroin) in 6 months prior (p=0.01) In 6-week arms patients with history of alcohol or drug use had similar adherence to those who had not used 58/60 (96.6%) achieved SVR Petersen et al. Hepatol Int. 2016

21 Take Home Points?

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23 Future exploration is needed into the agonist/antagonist mechanisms of cannabinoid CB receptors in the liver As a general rule, cannabis is not recommended for HCV patients Little data that cannabis use impacts HCV treatment adherence nor SVR rates