Alain H. Litwin, M.D., M.P.H. Irene J. Soloway, R.P.A.

Albert Einstein College of Medicine Montefiore Medical Center

November 2, 2012

Engaging Drug Users in Care andTreatment of Chronic Hepatitis C

Outline

• Why do we need integrated models of HCV Care?• HCV Peer Program at Einstein• Models of HCV Care at Einstein

– Multidisciplinary on-site treatment– Directly Observed Treatment (DOT)– Concurrent Group Treatment

• Case Study• Next Steps

Significance• IDUs are largest group of HCV-infected persons in

industrialized countries ~ 60% in U.S. (Shepard et al, 2005)– > 75% of new infections in IDUs– Up to 90% of IDUs in methadone clinics have HCV

• HCV prevalence in non-injecting DUs 2.3-17% (Sheinmann et al, 2007)

• Approximately 1200 opiate treatment programs (OTPs) and 265,000 patients in the United States.

• Over 1,000,000 patients have been prescribed buprenorphine in the United States.

Low Treatment Uptake among IDUs

• Before 2001, guidelines discouraged treatment of IDUs• Since 2002, revised guidelines advocate treating IDUs on a

case by case basis• However, HCV treatment rates among IDUs remain low:

overall rates of treatment uptake among IDUs: 1%- 6%– Baltimore cohort of 597 HCV-infected IDUs (Mehta et al, 2007)

• 70% aware of HCV treatment• 14% evaluated for treatment• 6% initiated treatment

– Vancouver community-based cohort of 2118 persons, mainly illicit drug users (Grebely et al, 2009)

• 64% HCV Ab+• 1.1% initiated treatment

Hepatitis C Treatment for IDUs: A Review of the Available Evidence (Hellard et al, 2009)

– Systematic review of 22 studies of pegylated interferon plus ribavirin in HCV-infected IDUs

• Median SVR rate among IDUs receiving PEG IFN + RBV: 54% • Similar SVR rates between IDUs and non-IDUs • In 3 large trials of treatment with PEG IFN + RBV (excluded

drug users): 54% - 63% SVR– 13 studies included IDUs in drug treatment programs

• Median SVR rate 48% • In 8 studies HCV treatment administered in multidisciplinary

programs providing care for HCV, addiction, and mental health

– Median SVR rate 49% (range 26%–94%)

Why do we need integrated models of hepatitis C care?

• 228 drug users (former and current) with chronic hepatitis C referred to liver clinic (Fishbein et al, 2004)– 127 (56%) accepted referral– 54 (24%) arrived for evaluation– 4 (2%) initiated treatment (no SVRs noted)

• 11% of patients with chronic hepatitis C who were evaluated at the liver clinic initiated antiviral treatment. (Feuerstadt et al, 2010)

• 76% of patients from opiate dependence treatment program interested in HCV treatment after hearing the risks and benefits. (Walley et al, 2005)

Why do we need on-site treatment?(Feuerstadt et al, 2010)

Genotype 1 - Group

SVR Unable to tolerate

Hispanic (n=92) 10.9% 31.5%

African-American (n=51)

13.7% 7.8%

Caucasian (n=16)

25.0% 31.2%

Annual age-adjusted mortality rates from hepatitis B and hepatitis C virus and HIV infections listed as causes of death in the United States between 1999 and 2007.

Ly K N et al. Ann Intern Med 2012;156:271-278

©2012 by American College of Physicians

SVR is Associated with Reduced Risk All-Cause Mortality (Backus et al; 2011)

Effectiveness vs Efficacy(El-Serag et al, 2010)

• BRONX

Integrating HCV care with opiate agonist treatment at Albert Einstein

• Network of community-sited opiate agonist treatment programs in the Bronx, NY

• Comprehensive on-site primary care

• 3400 patients– 59% Latino/a, 23% African American, 18%

Caucasian– 65% HCV Antibody positive– 50% chronic HCV infection

Integrating HCV Care with Opioid Agonist

Therapy at Einstein

Opiate Agonist Treatment

Site: Article 28 facility

Staff: Internist or family practice + PAPart-time psychiatristSubstance abuse counselors, HCV Coordinator and Educator, Social Worker and Nursing.

Services:Opioid agonist therapyComprehensive on-site 1º care General, HCV, HIV, GynPsych evaluation and treatmentSupport groups and peer educatorsLaboratory testing and EKGUrine toxicology testing

HospitalInterventional radiologistHepatologistTransplant centerPathologistEST, optho, derm, etc.Lab

Hepatitis C Evaluation and Treatment Protocol

• Universal testing - HCV antibody on all patients• HAV and HBV vaccines offered • Alcohol screening and counseling • HCV+ patients offered on-site evaluation and possible

treatment– protocol and AASLD guidelines

• Multidisciplinary team: medical providers (MD and PA), nurses, substance abuse counselors, and HCV staff (Program Coordinator and HCV Educator)

Roots“We represent a coalition of patients, providers, family members and friends: all affected by the hepatitis C epidemic in our South Bronx Community.

People in methadone maintenance must have access to hepatitis C resources. We work to ensure that current and former drug users have access to treatment for both substance abuse and

hepatitis C.”

Peer Program Evolution

HCV Peer Program

• Co-facilitation of groups (pre-treatment and group treatment)

• Escorts to liver biopsy and other off-site appointments (initiated by peer)

• Clinic events (e.g. recovery day)• Outreach within the clinic• Outreach within the community (health fairs, harm reduction programs, and primary care)

• Participation with advocacy activities (e.g. task force)

Liver Biopsy Program Results

• 100 patients scheduled (2005 – 2008)– Counseling and scheduling by Hepatitis Educator– 68% Male– 61% Latino; 32% African American; 7% Caucasian– 42% HIV/HCV coinfected

• 80 patients (80%) showed up to liver biopsy – some patients required multiple appointments (up to 3 referrals)

• 41 patients (41%) used escorts– Peers showed up 100% of the time

Methadone and Interferon(Berk et al, 2007)

Methadone and Telaprevir(van Heeswijk et al, EASL 2011)

Buprenorphine and Telaprevir(Luo et al, HEP DART 2011)

Integrated On-Site Treatment (n=73)

Retrospective, observational chart review of on-site HCVtreatment (pegylated interferon and ribavirin) provided to 73drug users between January, 2003 and December, 2005:

– 90% IDU– 49% recently used illicit drugs– 67% Latino, 21% Caucasian, and 12% African American– 32% HIV-infected– 67% current psychiatric illness– 40% advanced fibrosis on liver biopsy – 68% genotype 1– 38% attended HCV support groups

Litwin et al, 2005 and Litwin et al, 2009

HCV Treatment Outcomes

– 86% completed ≥12 weeks of treatment– 45% SVR

• Genotype 1 - 40% SVR– HIV/HCV coinfected equivalent SVR (43%) as

HCV-monoinfected patients (46%) – No association between illicit drug use during

HCV treatment and virological outcomes• active illicit drug use during treatment (37%)

How many patients can be evaluated and treated with an integrated model of care?

159 HCV + eligible for on-site services in one clinic, and 125(78%) chose on-site HCV care

• 83 with chronic hepatitis C (VL +)– 25 biopsies performed (7 required no

treatment due to low stage disease)– 21 initiated treatment, 8 (38%) achieved SVR– 17 with contraindications to HCV treatment– 45 (54%) reached primary goal of completion

of evaluation or treatment initiation

Harris et al, 2010

HCV DOT Study (Litwin et al, 2011)

Methods• Randomized, controlled trial• Subjects in both study arms receive once-weekly directly-

administered pegylated interferon injections• Subjects randomized to either ribavirin by directly observed

therapy (DOT) or treatment as usual (TAU)• Subjects in DOT arm receive between 3 and 6 directly

observed ribavirin doses weekly administered by nursing staff at same time and on the same schedule as subjects receive methadone. – Evening, non-clinic and weekend ribavirin doses individually packaged as take-

home doses.• Subjects in TAU arm self-administer twice-daily ribavirin at

home

Results (n=40)

Results (n=40)

Ribavirin adherence (n=40)Pill Count Adherence Rate

0.50

0.60

0.70

0.80

0.90

1.00

4 8 12 16 20 24

Week

DOT

TAU

Week DOT adherence (%) TAU adherence (%)

Week 4 90 78

Week 8 89 81

Week 12 88 80

Week 24 87 79

Ribavirin adherence (n=40)

• Mixed effects linear model– Study arm, time, and interaction

of study arm and time

• Over 24 weeks, pill count adherence higher for DOT than TAU subjects

• 88% DOT vs. 77% TAU (p =0.02)

Pegylated interferon adherence (n=40)

• Subjects in both arms received weekly directly administered pegylated interferon

• 96% DOT vs. 94% TAU(p=NS)

Treatment Outcomes

Treatment Outcomes

• SVR predicted based on following factors (data from large HCV trials)– Genotype (1/4 vs. 2/3)– HIV+ vs HIV-– Race/ethnicity (White, Black, Latino)– Treatment-naive vs treatment-experienced

• Predicted SVR = 37% (32% , 42%)• Actual SVR = 42% (34% , 50%)

DOT studies in United States -Opiate Agonist Treatment Programs

• Three U.S. DOT studies (Peg + RBV) demonstrate potential of DOT to increase rates of treatment initiation and SVR.

• Co-located model (Bruce et al, 2012): RCT of on-site DOT (Peg + RBV) (n=12) vs. off-site (n=9) – 12 of 12 in on-site DOT arm started treatment vs. 4 of 9 in off-site arm– 6 of 8 on-site DOT arm with SVR vs. 1 of 4 in off-site arm

• Off-site model (Bonkovsky et al, 2008): RCT of DOT (Peg only) (n=24) vs. self-administration (n=24). – Stepwise logistic regression analysis for SVR: (DOT vs. SA; OR 3.27,

95% CI 0.90–11.91, P = 0.073)• Off-site model (Taylor et al, 2012): Prospective trial of DOT (Peg +/- RBV)

Genotype 1 HIV/HCV coinfected patients (n=11)– 2 of 11 had SVR (18%)– 5 of 11 did not complete 12 weeks (45%)

Once Daily DOT with PEG/RBV in Drug Users (Waizmann, 2010)

• German retrospective study of 49 HCV mono-infected IDUs enrolled in an opiate agonist treatment program with integrated model (methadone or buprenorphine)– No recent illicit drug use– 57% genotypes 2 / 3; 43% genotypes 1 / 4– Median age 30.1 years; median duration of infection 3.4 years– median BMI 23.7– median HCV viral load = 121,775 IU/ml– no HIV

• Patients seen once daily and received DOT with PEG-IFN alfa-2a once weekly and daily fixed dose of ribavirin 800 mg – 1200 mg.

• All received citalopram (2 weeks prior to HCV treatment)• 98% achieved SVR (48 out of 49)• Safety profile of ribavirin once daily not different than twice daily dosing in

this population

HIV DOT Decreases Viral Load (Berg et al, 2011)

HCV Concurrent Group Treatment at Einstein 2009 - present

HCV Group Treatment at Einstein2009 - present

•Group orientations and individual HCV workup•Trial with placebo pillbox•4 - 12 patients form cohort and initiate treatment •Multiple cycles each year at two sites•Third site starting 2013•Flexible model: concurrent and rolling initiation•Both peg/ribavirin and triple therapy with DAAs•DOT with prepared pillboxes 60 patients as of October 2012

HCV Group Treatment Model

Peer / Health Educator

• Sets up room: coffee, snacks

• Side effect surveys done• Weights and vitals taken• Group discussion co-

facilitated by Peer Educator and Health Educator

Provider

• Conducts semi -private individual visits

• Vitals and focused physical• Addresses adverse effects and

adherence• Administers peg interferon

injections and growth factors as needed

Conclude with patient milestones, updates and peer led meditation

Incentives and Enhancements• Metrocards for initial 12 weeks• Coffee and snacks• Certificates and celebrations as patients complete

treatment milestones• Education/stories/games• Family friendly• Invited guests: physicians, students/residents,

organizations etc

HCV Group Treatment Tools

Group Treatment in Action

HCV Group Treatment with peg/ribavirin (n =27)

• First 27 patients treated with peg/ribavirin• 70% Latino• 66% Genotype 1• 30% HIV co-infected• 59% pre-existing psychiatric illness• >58% recently used illicit drugs

• High rates of group attendance / retention• 89% of those initiated completed all group sessions• 4 of 27 patients discontinued for adverse events

• Virologic results• 44% genotype 1 achieved SVR

• Includes co-infected, cirrhotic, co-morbid disease

Group Treatment Triple Therapy with Directly Acting Antivirals

• Telaprevir (Incivik) Boceprevir (Victrelis)

Q 7-9 hour dosing with 20 gram fat meal :4 hour window

Q 7-9 hour dosing with carb snack: 2 hour window

Group Treatment Results with Direct Acting Antivirals (n=28)

Retrospective, observational chart review of HCVtreatment (pegylated interferon, ribavirin, and DAAs)provided to first 28 drug users between 8/ 2011 and 9/2012

• 93 % IDU• 57% recent positive urine tox (within 6 months)• 75% Latino, 21% African American, 4% Caucasian• 89% current psychiatric illness• 100% genotype-1• 11% discontinued treatment early• 86% <43 IU/ml or undetectable viral load at 4 weeks• 89% undetectable viral load at 24 weeks (n=19)• 81% end of treatment response (n=16)

Group Treatment Benefits

For Patients

• Social support is built-in to

treatment

• Misconceptions addressed in

group discussions

• Reassurance by concurrent

participation of peers

• Fear of negative side effects

mitigated

• Side effects normalized

For Providers

• Frequent contact and close observation by providers and peers

• Co management of cohort enhances expertise and confidence

• Natural mentoring opportunity

• Break from “the usual”

HCV Group Treatment Model Benefits: Peer Education

• Patients acquire information before, during, and after treatment

• Patients learn to communicate their knowledge and experience to others

• Patients who complete treatment come back to support others and reinforce core messages

• Natural segue to more formal peer educator role

HCV Group Treatment: Challenges• Assembling cohort• Staff (Health Educator)• Protected time for Healthcare Provider • Funding (for metrocards)• Needs to be studied further

Case Study E.O.• 32 year old Latino male with history of PTSD and

substance abuse• First heroin use age 17 , first IDU age 19 • Therapeutic Community (T.C.)

→relapse →detox →bupe/recovery groups• Aware of HCV+ status from T.C.• “Interested in HCV treatment” →pre-treatment

workup• Genotype and viral load done, patient offered

treatment

Case Study E.O.

• Psychiatric assessment: “may need more time in recovery but no contraindications”

• Re-started on sertraline and quetiapine• Attended two HCV group treatment

orientations co-facilitated by peer educators

E.O: Treatment Course• Starts Group Treatment on triple therapy with telaprevir• Week 4: ↓5 grams hgb ↓10% weight loss, increased depression, rash• Initiated growth factors, marinol, topical

steroids, psychiatric medication adjustments• Patient arrested week 8: central booking: “I

need my 20 grams fat”

E.O. continued

• Patient gets married (wife also HCV+): brings wife to group on wedding day

• Graduates from outpatient drug treatment program

• Starts vocational training for electrical trade• Wife now seeking treatment for HCV

Benefits of ModelPatient drivenEducation by peers and providersMultidisciplinaryDOTPsycho-social supportSupport for recoveryRole modeling by peers“Upward spiral”

Einstein Model: Conclusions

• Drug users are interested in treatment, accept treatment recommendations, and are effectively treated.

• Integrated models of care involving peers, groups, and directly observed therapy (DOT) may be effective strategies to:– increase access to care – promote adherence , completion, and cure

• Adherence is more complex with triple therapy

Future Studies: Intensive Models of HCV Care for Injection Drug Users

• Randomize 150 treatment-naive (HIV/HCV coinfected and HCV monoinfected) genotype-1 patients to three models of on-site care– Standard on-site care– DOT – Concurrent Group Treatment

• Outcomes: Adherence, completion, cure, and resistance

• What levels of adherence prevent resistance?• Cost and cost-effectiveness of each model

IFN-Free Regimens for Treatment-naive

• 94% SVR12 with 12 weeks of IFN-free triple therapy for G1 treatment-naive patients-ABT450/r once daily (ritonavir-boosted NS3 protease

inhibitor) + ABT333 twice daily (non-nucleoside NS5B inhibitor) + RBV

• 100% SVR4 with 24 weeks of IFN-free double therapy regimen for G1 treatment-naive patients-Daclatasvir once daily (NS5A inhibitor) + GS7977 once daily

(nucleotide NS5B inhibitor)

Drug Interaction Chart

Gloria Searson, MSW: Founding Director , Coalition for Positive Empowerment (COPE)

“With all of this exciting information, there is nothing

exciting for them.”

Theory of Fundamental CauseDisparities in Care (Link and Phelan)

• SES is a “fundamental cause” of health and mortality disparities– money, knowledge, prestige, power, social connections

• SES disparities endure despite availability of more effective treatment

• When treatments more efficacious, disparities increase• In U.S., health care fragmented for all people, but people with

high SES mobilize necessary resources• Intensive models of HCV care which mobilize resources may

decrease associations between SES and HCV-related morbidity and mortality

2009 AASLD Guidelines: Drug Users

“Treatment of HCV infection can be considered for persons even if they currently use illicit drugs or who are on a methadone maintenance program, provided they wish to take HCV treatment and are able and willing to maintain close monitoring…Persons who use illicit drugs should receive continued support from drug abuse and psychiatric counseling services as an important adjunct to treatment of HCV infection”

Addiction treatment physicians and HCV treatment eligibility

Integrated Models with Multidisciplinary Care and Peer Support (Grebely et al, 2010)

• 204 HCV Antibody+ illicit drug users within a clinic in Vancouver, Canada who accepted referral to a weekly HCV peer-support group– 53% of patients received HCV evaluation– 28% (n=50) received HCV treatment – 63% (n=19) SVR among those completing treatment

despite illicit drug use in 53%– First 4 weeks of support group attendance (2-4 groups

versus 1 group) predicted successful HCV assessment (OR: 6.0; 95% CI 3.3-11.1)

2009 AASLD Guidelines: Alcohol

“Treatment should be individualized for people who currently use alcohol and who are willing to participate in a substance abuse or alcohol treatment program.”

Integrated Care Model – Alcohol Dependence

(Le Lan et al, 2012) • Prospective, observational, case-controlled study of patients (n=73) of

HCV patients with alcohol dependence (ongoing consumption or < 6 months of abstinence)– 62% drinking at time of treatment– 34% abstinent < 3 months

• SVR 48% in patients with alcohol dependence vs 49% of controls

• Length of abstinence PRIOR to treatment did not predict SVR

• During HCV treatment, length of abstinence associated with SVR– abstinent (30%) – 65% SVR, – Low-risk consumption (34%) – 52% SVR– excessive consumption (36%) – 33% SVR

Scaling Up in the United States• 1200 opiate treatment programs (OTPs) - 265,000 patients• Over one million patients prescribed buprenorphine • Majority of programs don’t offer HCV testing or treatment

either on-site or by contractual agreement (Bini et al, 2012)• Only 7.1% of patients receiving long-term treatment at OTPs

had regular contact with primary care provider.• National survey of addiction treatment physicians (Litwin et

al, 2007)– 9% providing on-site HCV treatment without referral– additional 31% willing if given appropriate training and resources

Integrated Models of Care – Centralized Models

• Models of care take advantage of existing resources and access to patients with chronic hepatitis C– VA is a model program– Primary care centers such as FQHCs – Substance abuse treatment clinics– HIV clinics– Corrections– Other: mental health centers, mobile vans, shelters

Integrated Models of Care -Decentralized Models

• Intensive Case Managers and Patient Navigators (Edlin and Carden; Check HepC Program in New York City)

• Peer escorts (Litwin et al, 2005)• Telemedicine (Arora et al, 2011)• Contingency Management

– Modest compensation (e.g. $20) for attending appointments combined with other strategies

• TB Clinic Infrastructure

Future Directions (Gravitz, 2011)

Future Directions (Edlin, 2011)

Effectiveness vs Efficacy(El-Serag et al, 2010)

AcknowledgementsDoSA HCV Program Staff DoSA HCV Treatment TeamLauren Cockerham-Colas Medical AssistantsSheila Reynoso NursesRobert Roose PhysiciansMelissa Stein Physicians AssistantsPeer Leaders and Advisors Substance Abuse Counselors

HCV DOT Study DoSA Executive StaffJulia Arnsten Valerie BartlettAbigail Batchelder Sarah ChurchMichael Ciofoletti Ira MarionJoe HechtJennifer HidalgoMoonseong HeoXuan Li

Acknowledgements

• National Institute of Drug Abuse• Robert Wood Johnson Foundation• New York State Department of Health• New York City Department of Health• Centers for Disease Control and Prevention

Reasons patients not offered HCV treatment

71 (49%) patients not offered treatment

– mild liver fibrosis on biopsy (14)– AIDS - low CD4 count (14)– unstable chronic illnesses (14): cardiac disease (4); pulmonary disease (4); seizure

disorder (2); renal insufficiency (2); diabetes (1); hypertension (1)– decompensated cirrhosis (4)– malignancies (4): hepatocellular carcinoma (1); gastric carcinoma (1) ; multiple

myeloma (1); metastatic cervical carcinoma (1)– cytopenias (4): anemia (2); thrombocytopenia (2)– Insurance not accepted (4)– unstable drug use (3)– severe alcohol dependence (3)– unstable psychiatric illness (2)– autoimmune conditions (2): CREST syndrome(1); rheumatoid arthritis (1)– other illnesses (2): pancreatic fistula (1); abscess after hip replacement (1)– lost to follow-up (1)

Drug Use Prior to Treatment and Adherence (Sylvestre et al, 2007)

Drug Use During HCV Treatment and Adherence(Sylvestre et al, 2007)

HIV DOT: Association between frequent drug use, treatment arm, and adherence (Nahvi et al, 2011)

HCV Group Treatment Model Benefits: Peer Education

•Patients acquire information before, during, and after treatment

•Patients learn to communicate their knowledge and experience to others

•Patients who complete treatment come back to support others and reinforce core messages

•Natural segue to more formal peer educator role

Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks

Combination Therapy for Null Responders

1. Lok A, et al. EASL 2011. Abstract 1356.2. Chayama K, et al. AASLD 2011. Abstract LB-4.

100

80

60

40

20

0

36

Daclatasvir + Asunaprevir

Daclatasvir + Asunaprevir + PR

SV

R24

(%

)

90 90*

N/A

US Study[1] Japan Study[2]

*all genotype 1b patients.

Determinants of Successful Treatment with DAAs

• Treatment-naive vs. treatment-experienced• HCV subtype 1b vs. 1a• IL28B genotype CC vs. CT or TT genotypes• Drug potency and resistance barrier• Drug concentration (DDIs)• Liver histology: no cirrhosis vs. cirrhosis• Baseline resistance• Adherence to treatment• Aggressive side effect management• Drug safety and tolerability