1. Treatment of HCV infection among active IDUs Jason Grebely, PhD Lecturer Viral Hepatitis Clinical Research Program National Centre in HIV Epidemiology and Clinical Research University of New South Wales

2. Hepatitis C treatment IFN-α2b 24 weeks 8%-12% PEG-IFN 48 weeks 25%-29% IFN-α2b 48 weeks 15%-22% IFN-α2b+RBV 48 weeks 41% PEG-IFN+RBV 24-48 weeks 61%-65% 10 years ? Sustained virologic response

3. Management of Hepatitis C 1997 NIH Consensus Development Conference Statement: “treatment of patients who are drinking significant amounts of alcohol or who are actively using illicit drugs should be delayed until these habits are discontinued for at least 6 months” 3 National Institutes Of Health Consensus Development Conference Statement. March 24- 26, 1997. Available at: http://consensus.nih.gov/1997/1997HepatitisC105html.htm Accessed September 19, 2009.

4. Treatment of HCV in IDUs Treatment initiated during opiate detoxification treatment (n=50) –IFN alfa-2a (n=34) –IFN alfa-2a + RBV (n=16) Drug use: –ICD-10 opiate dependency –36% cocaine (>weekly) Treatment completion: 46% Overall SVR: 36% 80% relapsed to drug use –SVR: 24% vs 53% 4 Backmund et al. Hepatology 2001. 0 10 20 45% 6% SVR (%) 30 40 50 60 70 80 90 100 >2/3 Appointments <2/3 Appointments P<0.05

5. Treatment of HCV in IDUs Treatment of HCV during methadone maintenance therapy (interim analysis) IFN alfa-2b + RBV (n=50) Mean age 50, 62% psych history, 62% markers of advanced disease, 52% genotype 1 78% completed HCV treatment 5 Sylvestre D, et al. Drug and Alcohol Dependence 2002. 54% Poynard 1998 McHutchison 1998 Overall ETR (%) 0 20 40 60 80 100 G1 Non-G1 36% 70% 51% P>0.05

6. NIH Revises Recommendations 2002 NIH Consensus Statement: –Management of HCV is enhanced by linking to drug- treatment programs –Methadone is not a contraindication to HCV treatment –HCV treatment of active IDUs should be considered on a case-by-case basis –Active IDU in and of itself should not exclude such patients from antiviral therapy 6 NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed September 19, 2009.

7. Treatment uptake among IDUs is still low 7 nCohortHCV Treatment Uptake/Year Canada (Vancouver)1,360Community-based inner city residents <1% United States (Baltimore)597Community-based IDUs<1% Australia2,500Needle exchange participants 1% Grebely J, et al. J Viral Hepatitis 2009. Mehta S, et al J Community Health 2008. National Centre in HIV Epidemiology and Clinical Research 2008.

8. IDUs demonstrate high HCV treatment willingness 8 Stein MD, et al. Drug and Alcohol Dependence 2001. Walley AY, et al. J Substance Abuse Treatment 2005. Doab A, et al. Clinical Infectious Diseases 2005. Fischer B, et al. Presse Med 2005. Strathdee S, et al Clinical Infectious Diseases 2005. Grebely J, et al. Drug and Alcohol Dependence 2008.

9. Barriers to seeking treatment for HCV infection The major reasons for not having sought treatment were: –Lack of information/did not know that treatment was available (23%) –Absence of symptoms (20%) –Perceived side effects of treatment (14%) –Mild liver disease (10%) –Other medical co-morbidities (8%) –Lack of interest in treatment (3%) 9 Self-reported current HCV positive status (n=188) Never sought treatment for HCV infection (n=107, 57%) Grebely J, et al. Drug and Alcohol Dependence 2008.

10. Barriers to HCV treatment uptake are multi-factorial Barriers to HCV treatment access may relate to: –lack of knowledge and low prioritisation among patients –limited HCV treatment infrastructure, particularly in settings of drug dependency treatment –lack of treatment consideration or active discrimination by clinicians 10

11. Remains a reluctance to treat IDUs for HCV Concerns of: –Adherence –Ongoing drug use –Relapse to substance use –Risk of exacerbation of co-morbid psychiatric disease –Perceived risk of HCV reinfection following successful treatment 11

12. Treatment of HCV in IDUs 12 Hellard M, et al. Clinical Infectious Diseases 2009. Median SVR –Regardless of treatment regimen: 40.6% –Peg-IFN alfa + RBV: 54.3%

13. Impact of adherence on SVR Methadone maintenance (n=71) IFN alfa-2b+RBV Adherence: 80/80/80 59% used illicit drugs during treatment –35% used heroin, cocaine, or methamphetamine 68% (n=48) were adherent 13 0 10 20 42% 4% SVR (%) 30 40 50 60 70 80 90 100 Adherent Nonadherent P=0.001 Sylvestre D, et al. European Journal of Gastroenterology and Hepatology 2007.

14. Impact of ongoing drug use on adherence 14 Sylvestre D, et al. European Journal of Gastroenterology and Hepatology 2007.

15. Discontinuation occurs early in therapy 15 Observational study of MMT (n=50) vs. controls (n=50) SVR was 42% in MMT vs. 56% in controls No significant increase in methadone dose during therapy Methadone - All Methadone - Noncompliance Controls - All Controls - Noncompliance Mauss S, et al. Hepatology 2004.

16. Treatment completion 16 Hellard M, et al. Clinical Infectious Diseases 2009. Median completion overall: 70.7% Only 1 of 5 evaluable studies demonstrated a difference in treatment completion rates in IDUs vs. non-IDUs

17. Adherence Poor data on adherence Varying definitions of adherence makes it difficult to compare studies 17 Hellard M, et al. Clinical Infectious Diseases 2009.

18. Adherence failure…. 18 A “bad patient?” or …... our failure to design a treatment program which works for that individual

19. Directly observed therapy for HCV 19 Grebely J, et al. Journal of Gastroenterology and Hepatology 2007. Study Design: Open label, prospective, observational trial Primary Endpoint: Proportion with undetectable HCV RNA 6 months after treatment (SVR) N = 40 Week 48 for genotype 1; Week 24 for genotypes 2/3 Interferon alfa-2b 3 MIU 3x/week + Ribavirin 800-1200 mg/day (n = 12) Peginterferon alfa-2b 1.5 µg/kg/week + Ribavirin 800-1200 mg/day (n = 28) Medication administration: IFN (3x week) and PEG-IFN (1x week) were administered as DOT RBV self-administered

20. Directly observed therapy for HCV 20 Grebely J, et al. Journal of Gastroenterology and Hepatology 2007. Mean age 43, 83% male, 55% genotype 2/3 Early discontinuation - 11 patients (28%) 35% used illicit drugs in the last 6 months 48% used illicit drugs during treatment

21. Impact of prior and ongoing IDU on SVR Grebely J, et al. Journal of Gastroenterology and Hepatology 2007. 35% used illicit drugs in the last 6 months 48% used illicit drugs during treatment “frequent” – greater than weekly 21

22. Impact of prior and ongoing IDU on SVR 22 Sylvestre D, et al. Journal of Substance Abuse Treatment 2005. IFN alfa-2b + RBV during methadone maintenance (n=76) 36% used illicit drugs during treatment “frequent” - everyday or every other day for a min of 1 month

23. Impact of IDU and adherence on SVR 23 Australian Trial in Acute Hepatitis C Study (n=109), 74 HCV Dore G, et al. Gastroenterology 2010.

24. Enhancing HCV treatment through peer support From March 2005 to 2008, HCV-infected individuals were referred to a weekly peer-support group and assessed for HCV infection (n=204 accepted referral). Assessment for HCV in 53% The first 4 weeks of support group attendance predicted successful HCV assessment (OR: 6.03, 95% CI:3.27–11.12, P<0.001) Treatment for HCV was initiated in 28% (n=57) 24 Grebely J, et al. J European Gastroenterology and Hepatology 2009 (In Press).

25. Conclusions Treatment of HCV among current and former IDUs is effective –Studies to date are limited by small sample size and absence of prospective, longitudinal data collection Treatment completion/adherence –Comparable rates of treatment completion between IDUs and non-IDUs –Adherence has an impact on SVR Drug use during treatment –Drug use prior to treatment is not associated with reduced SVR –Frequent drug use may be associated with reduced response to therapy –Cannot predetermine who will discontinue due to drug use prior to initiation of treatment –Must evaluate patients on a case by case basis 25

26. There is still much to learn.... Current uptake of assessment and treatment among IDUs is still unacceptably low –Why are IDUs assessed for HCV infection not receiving treatment? Treatment is effective –What factors are associated with response? Treatment completion/adherence –Evaluation of strategies to enhance adherence (e.g. Individualized treatment, DOT) Drug use prior to and during treatment –What is the impact of drug use on treatment for HCV infection? There is still concern about HCV reinfection following HCV treatment –Factors associated with reinfection? 26