Download Plenary – Litwin_Soloway 2012

Engaging Drug Users in Care and
Treatment of Chronic Hepatitis C
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
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
Hispanic
(n=92)
AfricanAmerican
(n=51)
Caucasian
(n=16)
10.9%
Unable to
tolerate
31.5%
13.7%
7.8%
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 AllCause 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:
Staff:
Article 28 facility
Internist or family practice + PA
Part-time psychiatrist
Substance abuse counselors,
HCV Coordinator and Educator,
Social Worker and Nursing.
Services:Opioid agonist therapy
Comprehensive on-site 1º care
General, HCV, HIV, Gyn
Psych evaluation and treatment
Support groups and peer educators
Laboratory testing and EKG
Urine toxicology testing
Hospital
Interventional radiologist
Hepatologist
Transplant center
Pathologist
EST, 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 HCV
treatment (pegylated interferon and ribavirin) provided to 73
drug 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 directlyadministered 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 takehome 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
1.00
0.90
0.80
DOT
0.70
TAU
0.60
0.50
4
8
12
16
20
24
Week
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 Einstein
2009 - 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
Provider
• Sets up room: coffee,
• Conducts semi -private
snacks
• Side effect surveys done
• Weights and vitals taken
• Group discussion cofacilitated by Peer
Educator and Health
Educator
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)
Q 7-9 hour dosing with 20 gram fat meal
:4 hour window
Boceprevir (Victrelis)
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 HCV
treatment (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 Model
Patient driven
Education by peers and
providers
Multidisciplinary
DOT
Psycho-social support
Support for recovery
Role 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 Cause
Disparities 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)
Acknowledgements
DoSA HCV Program Staff
Lauren Cockerham-Colas
Sheila Reynoso
Robert Roose
Melissa Stein
Peer Leaders and Advisors
DoSA HCV Treatment Team
Medical Assistants
Nurses
Physicians
Physicians Assistants
Substance Abuse Counselors
HCV DOT Study
Julia Arnsten
Abigail Batchelder
Michael Ciofoletti
Joe Hecht
Jennifer Hidalgo
Moonseong Heo
Xuan Li
DoSA Executive Staff
Valerie Bartlett
Sarah Church
Ira Marion
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
Combination Therapy for Null Responders

Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032)
BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks
US Study[1]
100
90
Japan Study[2]
Daclatasvir + Asunaprevir
90*
Daclatasvir + Asunaprevir + PR
SVR24 (%)
80
60
40
36
20
0
1. Lok A, et al. EASL 2011. Abstract 1356.
2. Chayama K, et al. AASLD 2011. Abstract LB-4.
N/A
*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