Heroin use is associated with progression to cirrhosis in HIV-HCV co-infected patients

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1 Heroin use is associated with progression to cirrhosis in HIV-HCV co-infected patients 7 th HIV & Hepatitis Co-infection workshop Milan, June 2011 Laurence Brunet, Erica Moodie, Kathleen Rollet, Mark Tyndall, Curtis Cooper, Sharon Walmsley Neora Pick, Marina B. Klein for the Canadian Co-infection Cohort (CTN222)

2 Background There are limited data on the effects of tobacco and marijuana smoking on hepatic fibrosis Cross-sectional studies suggest smoking of either may be associated with fibrosis in HCV mono-infected populations There is no data on the effect of heroin or cocaine or use on fibrosis in co-infected persons Heroin and cocaine use may cause liver damage through oxidative stress or toxic contaminants

3 Objectives To evaluate the association between tobacco, marijuana, injection cocaine or injection heroin use and progression of liver fibrosis or cirrhosis in a prospective cohort study of HIV-HCV coinfected patients.

4 Methods Design The Canadian HIV/HCV Co-infection Cohort (CCC; CTN222) is an ongoing prospective multi-centre study enrolling participants (n=955) from 16 centers across Canada from 2003 Participants provide information on sociodemographic factors, clinical care and risk behaviours by completing questionnaires approximately and undergo blood tests every 6 months. Eligible subjects for the study were free of liver fibrosis, cirrhosis (as assessed clinically or by APRI <1.5) at baseline (n=725)

5 Methods Assessment of exposure Self-reported use of tobacco, marijuana, injection cocaine and heroin recorded at each visit Assessment of outcome AST to platelet ratio index (APRI) Significant liver fibrosis two consecutive APRI scores st APRI scores 1.5 Liver cirrhosis two consecutive APRI scores 2 1 st APRI scores 2

6 Results Baseline characteristics Median (IQR) or N (%) Follow-up years 2.4 ( ) Age (years) 44 (39-49) Male 518 (71) Duration of HCV infection (years) 18 (11-25) CD4 cell count (ul) 390 ( ) HIV viral load <50 copies/ml 387 (54) APRI score 0.50 ( ) Alcohol user 342 (47) Tobacco smoker 553 (77) Marijuana smoker 374 (52) Cocaine user (injection) 247 (34) Heroin user (injection) 135 (19)

7 Association with liver fibrosis Time-dependent Cox proportional hazards Fibrosis event defined as two consecutive APRI scores 1.5 Exposure HR (95% CI)* Current self-reported heroin use** 2.07 ( ) Current self-reported tobacco use 1.40 ( ) Current self-reported marijuana use 0.60 ( ) Current self-reported cocaine use** 1.71 ( ) *Adjusted HR for sex, duration of HCV infection at baseline, current alcohol use and CD4 cell counts ** Adjusted for cocaine or heroin use, respectively; Adjusted for cocaine and heroin use

8 Association with liver cirrhosis Time-dependent Cox proportional hazards Cirrhosis event defined as two consecutive APRI scores 2 Exposure HR (95% CI)* Current self-reported heroin use** 3.98 ( ) Current self-reported tobacco use 2.46 ( ) Current self-reported marijuana use 0.42 ( ) Current self-reported cocaine use** 1.44 ( ) *Adjusted HR for sex, duration of HCV infection at baseline, current alcohol use and CD4 cell counts ** Adjusted for cocaine or heroin use, respectively; Adjusted for cocaine and heroin use

9 Role of other Covariates Fibrosis Exposure HR (95% CI) Male 1.03 ( ) Baseline HCV duration 0.99 ( ) Current alcohol user 1.60 ( ) CD4 count (per 100 cell/ul) 0.82 ( ) Cirrhosis Exposure HR (95% CI) Male 0.57 ( ) Baseline HCV duration 0.96 ( ) Current alcohol user 1.98 ( ) CD4 count (per 100 cell/ul) 0.70 ( )

10 Conclusion Similar results obtained using the less stringent definition of fibrosis and cirrhosis Co-infected self-reported heroin users were almost four time more likely to progress to cirrhosis, compared to non-users Tobacco, marijuana and IV cocaine use were not significantly associated with progression to fibrosis or cirrhosis

11 Discussion Ultrastructural changes observed in the liver of 40 intravenous heroin addicts compared to the liver of 10 young healthy controls (Ilic, 2010) Chronic IV heroin use causes an increased synthesis of enzymes of smooth endoplasmic reticulum (SER) Results in hyperplasia and hypertrophy of the SER In cases of chronic active hepatitis and cirrhosis: Presence of continuous basal membrane and transformation of sinusoids into capillaries, causing disorders of microcirculation and further progress of cirrhosis There are no data on the effects of heroin on progression to fibrosis or cirrhosis in co-infected patients

12 Future work Investigate the effect of cumulative exposure and the presence of a dose-response relationship Investigate the effects of non-injected opioids (? class effect) Investigate the presence of effect measure modification by alcohol and other substances use as cirrhosis was more frequent among heroin addicts who used non-narcotic drugs, possibly due to mixed intoxication (Passarino 2005) Validate the results using a marginal structural model to better control for confounding

13 Acknowledgments The participants of HIV-HCV Canadian Cohort (CTN 222) The Co-Investigators: Dr. s Anita Rachlis, Brian Conway, Curtis Cooper, Danielle Rouleau, David Haase, David Wong, Erica Moodie, Jeff Cohen, Joe Cox, John Gill, Julio Montaner, Marianne Harris, Mark Hull, Mark Tyndall, Martin Potter, Neora Pick, Pierre Côté, Roger Sandre, Shariq Haider and Sharon Walmsley Study Coordinators