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TRANSCRIPT
Adherence in the Age of HCV An1viral Therapy
Jeffrey J. Weiss, PhD, MS Icahn School of Medicine at Mount Sinai
Disclosures
• No disclosures
Goal of lecture: • Review the current state of knowledge about adherence to HCV treatment
• Discuss its relevance as treatment moves towards all oral an<viral therapy
Medicine Men, Daniel Goldstein
Grebely, J., Dore, G.J. Can hepatitis C virus infection be eradicated in people who inject drugs? Antiviral Research, 2014, 104:62 – 72.
Hepa11s C Virus (HCV)–Infected Persons in the United States and Es1mated Rates of Detec1on, Referral to Care, and Treatment.
Holmberg, S.D. et al., 2013;368:1859-1861.
Barriers to Treatment Ini1a1on
• Pa<ent-‐level barriers • Provider-‐level barriers • Structural barriers
Hepa11s C is a Disease of Marginalized Groups
Rates of infec<on: • IDU > 10 years of use 90% (Tseng et al. 2007) • IDU < 9 years of use 66% (Tseng et al. 2007) • Homeless persons 19-‐69% (Chak et al. 2011) • Prisoners 29% (Larney et al. 2013) • Severely mentally ill 20% (Rosenberg et al. 2001) • US popula<on 2%
Forget me not
OPen ForgoRen
Clinical Trials vs Real World Experience
Clinical trials Real world
PEG/RBV* 46% (1) 14% (2)
PEG/RBV + telaprevir** 75% (3) 43% (4)
* Data as SVR24 ** Data as SVR24 for (3) and SVR12 for (4)
(1) Fried MW et al, NEJM 2002;347:975 (2) Feuerstadt P et al, Hepatology 2010;51:1151 (3) Jacobson IM et al, NEJM 2011;364:2405 (4) Bichoupan K et al, EASL 2013:A795
Diagram of Patient Flow Through Treatment Stages (HCV-selected samples)
Carol S. North et al. Hepatitis C treatment and SVR: the gap between clinical trials and real-world treatment aspirations. General Hospital Psychiatry, 2013, 35, 2, 122 - 128
Medica1on Acceptance
Patient-level Depression/Psychiatric Substance Use Cognitive functioning Social Support Illness Perceptions Medication Beliefs
Adherence System-level Insurance coverage Co-payments Provider Relationship Clinic/Practice Pharmacy Services Stigma Policy Stock-outs
Adverse Effects Side-effects Side-effect management
Determinants of Adherence
Regimen Number of pills Size of pills Dosing frequency Length of treatment
Patient
Pharma
Providers Insurance Co. Government Community
Resistance
• Gene<c barrier (higher in genotype 1b than 1a)
• Pharmacologic barrier -‐ nucleo(s)<de polymerase inhibitors have a high barrier whereas non-‐nucleoside polymerase have low barrier
• Pa1ent Adherence
Resistance
• Resistant variants are detectable in the majority of pa<ents with treatment failure to NS3 protease inhibitor-‐ or NS5a inhibitor-‐based an<viral therapy
• Resistant variants disappear in the majority of pa<ents, with median <me to loss of muta<ons of 4-‐64 weeks
• Retreatment with a different class of DAAs aWer failure of NS3 PI-‐based therapy has been successful in small studies
Schneider & Sarrazin, Antiviral Research, in press
Time Course of IFN Side Effects
0 4 5 11 12
IFN Treatment (Weeks)
Seve
rity
6 7 8 9 10 1 2 3
Fatigue Flu-like symptoms
Depressive/ anxiety
symptoms
Safety Summary PHOTON-‐1 223 HIV-‐co-‐infected subjects
Sofosbuvir + Ribavirin
AEs in > 10% of subjects 24 weeks (n=155) naïve gen 1 and experienced gen 2,3
12 weeks (n=68) naïve gen2,3
Fa<gue 39 35 Insomnia 15 21 Headache 14 13 Nausea 15 18 Diarrhea 11 9 Irritability 10 10 URI 12 12
#26 S. Naggie et al. CROI 2014
Safety Summary PEARL III phase 3 study of 419 gen 1b naïve
ABT-‐450/ritonavir + ABT-‐267 + ABT-‐333
AEs 3 DAA + RBV (n=210) 12 weeks
3 DAA (n=209) 12 weeks
Headache 24 23 Fa<gue 21 23 Pruri<s 12 5 Nausea 11 4 Asthenia 11 5 Insomnia 9 3
#29LB Reddy et al. CROI 2014
Adherence Decreases as Dosing Frequency Increases
Saini et al. (2009) Effect of Medication Dosing Frequency on Adherence in Chronic Diseases. Am J Man Care, 15, E22-E33.
Systematic Review 1986-2007 – 20 studies Prospective design, Chronic Disease, MEMS adherence assessment
AVIATOR -‐ Adherence Data
• Phase 2b trial, 327 gen 1 naïve and experienced • Various 3 DAAs +/-‐ RBV for 8, 12, 24 weeks • Electronic monitoring – 4 bocles
#1096 Bourliere et al. AASLD 2013
#1096 Bourliere et al. AASLD 2013
NIAID Synergy Trial Adherence Data
• 60 naïve gen 1 – 3 arms – phase II trial • 88% black, 72% male, 61% less than 12th grade • Psychiatric disease (43%); recent drug/ETOH abuse (37.5%)
• Sofosbuvir + Ledipasvir (FDC) 12 weeks 1 pill QD (n=20)
• FDC + GS9451 6 weeks 2 pills QD (n=20) • FDC + GS9669 6 weeks 3 pills QD (n=20) • Adherence measured using MEMS, pill counts and pa<ent report
#667 Petersen et al. CROI 2014
NIAID Synergy Trial Adherence Data 2
• MEMS Adherence declines with increasing pill burden (p=0.02) [99.3, 97.2, 94.8]
• MEMS Adherence declines during 12-‐week treatment (p=0.04) [98.1 0-‐4 vs. 95.0 8-‐12]
• Common reasons for non-‐adherence were feeling that drugs were working (39%), forgemng (35%) and absence from home (32%)
#667 Petersen et al. CROI 2014
Total Drug Exposure
Quality of Execu1on (Missed Doses/Injec1ons) Dosing Adherence (7-‐9 hours) Dietary Adherence
Dose Reduc1ons
Persistence (Early Treatment Discon1nua1on) Nonresponse
Side Effects (Pa1ent and/or Provider Decide to Discon1nue)
Weiss et al. (2009) Alim Pharmacol Ther , 30, 14-‐27.
Total Drug Exposure
Quality of Execu1on Dosing Adherence
Persistence (Early Treatment Discon1nua1on) Nonresponse
Side Effects (Pa1ent and/or Provider Decide to Discon1nue)
Differences between HCV and HIV: Implica1ons for Adherence Challenge
• Goal of HCV treatment is cure; whereas cure is not (yet) possible in HIV
• HCV treatment is <me-‐limited; whereas HIV treatment is life-‐long • If pa<ent is adherent and not resistant to medica<on, HIV
treatment works whereas this is not necessarily the case with HCV treatment
• HCV treatment can include dose reduc<ons and complex sequencing of medica<ons
• HCV treatment is not accompanied by a ‘Lazarus effect’; to the contrary
HCV Adherence Challenge • There are higher rates of psychiatric and substance use
disorders and cogni<ve impairment in persons with chronic HCV infec<on than in the general popula<on
• These have been shown to be risk factors for medica<on medica<on nonadherence in pa<ents with HIV
• PEG-‐IFN/RBV causes neuropsychiatric symptoms (depression, anxiety, emo<onal lability, irritability, insomnia) in a high percentage of treated pa<ents and can result in dose reduc<ons and early treatment discon<nua<on
Hepa11s C Pa1ents’ Self-‐reported Adherence to Pegylated Interferon and Ribavirin
Weiss et al. (2008) Alim Pharmacology & Ther
In a sample of 180 patients on treatment for Hepatitis C (23% co-infected with HIV): à 7% reported missing at least one injection of pegylated
interferon in the last four weeks à 21% reported missing at least one dose of ribavirin in
the last 7 days
Relationship Between Adherence to Hepatitis C Virus Therapy and Virologic Outcomes: A Cohort Study. Lo Re V 3rd et al. Ann Intern Med. 2011;155(6):353-360
Propor1on of pa1ents with early virologic response at each level of adherence to therapy with pegylated interferon and ribavirin over the ini1al 12 weeks, by HCV genotype
Adherence to assigned dosing regimen and sustained virological response among chronic hepa11s C genotype 1 pa1ents treated with boceprevir plus
peginterferon alfa-‐2b/ribavirin
Gordon SC, et al. Alimentary Pharmacology & Therapeutics Volume 38, Issue 1, pages 16-27, 26 MAY 2013
All adhered to >80% of treatment duration
Hepa11s C infec1on, an1viral treatment and mental health: A European expert consensus statement
Mar<n Schaefer et al. Journal of Hepatology, Volume 57, Issue 6, 2012, 1379 -‐ 1390
Mental Health & Substance Use
Dependence or Abuse
No past year mental illness
Any mental illness past year
Any illicit drugs 13.2 % 26.7 % Marijuana 10.3 % 19.5 % Cocaine 1.4 % 4.0 %
2012 National Survey on Drug Use and Health (NSDUH) N=68,309 noninstitutionalized adults
Inclusion criteria:
Prospec1ve Study of Adherence to HCV Treatment in HCV and HCV/HIV Pa1ents
(MH071177)
Exclusion criteria:
1) Chronic infec<on with HCV 2) Clinician and pa<ent decide to begin PEG-‐IFN/RBV therapy in
the next two months 3) Age 18 years or older 4) Primary language is English or Spanish
1) Prior treatment with interferon for HCV 2) Status post liver transplant
Subjects assessed at: Baseline (within one week prior to beginning PEG-‐IFN/RBV
therapy) 12 weeks aWer beginning therapy 24 weeks aWer beginning therapy
Assessments: Depression, Fa<gue, Physical Symptoms Psychiatric Disorders and Substance use – Current, Life<me – Structured Interview Medica<on Adherence, Treatment Self-‐efficacy Neuro-‐cogni<ve func<oning Chart Review through end of treatment (if early) or to 6 months post-‐end of treatment
Subject Life1me Psychiatric Characteris1cs
Total (n=78)
HCV/HIV- coinfected
(n=32)
HCV mono- infected (n=46)
Signifi-cance
OR (95%)
Substance use diagnosis lifetime (%)
75.6 65.6 82.6 p = 0.09 0.4 (0.1 -1.2)
Psychiatric diagnosis lifetime (%)
67.9 65.6 69.6 p = 0.71 1.2 (0.5 -3.1)
IVDU lifetime (%) 50.0 56.3 45.7 p = 0.36 1.5 (0.6 - 3.8)
Psychiatric hospitalization (%)
21.8 18.8 23.9 p = 0.59 0.7 (0.2 - 2.2)
Suicide attempt (%) 16.7 15.6 17.4 p = 0.84 0.9 (0.3 – 3.0)
History of Incarceration (%)
53.8 46.9 58.7 p = 0.30 0.6 (0.3 – 1.5)
Psychiatric Diagnoses at Time of HCV Treatment Ini1a1on
P=0.004
No lifetime psych/SU diagnosis
Lifetime psych/SU diagnosis – not present
Present psych/SU diagnosis
HIV/HCV (n=32)
6 (19%) 20 (62%) 6 (19%)
HCV (n=46)
5 (11%) 15 (33%) 26 (57%)
Baseline Depression/Fa1gue/Cogni1on
HIV/HCV (n=32)
HCV (n=46) Significance
Depression – BDI-II
6.7 (6.4) 11.7 (11.5) P=0.02
Depression-HAM-D
4.8 (4.3) 8.4 (6.5)
P=0.004
Fatigue – FSS 26.6 (15.8) 34.3 (16.5) P=0.04
Cognition – Global NP Score
40.9 (6.7) 41.6 (5.3) P =0.62
Perry et al. AASLD 2011
Logis1c Regression – Treatment Discon1nua1on by week 24
Variable OR 95% CI Significance
Age 0.9 0.9-‐1.1 0.31
HIV status 2.0 0.4-‐11.5 0.42
Sex 0.4 0.04-‐3.5 0.41
Black vs. other 3.9 0.7-‐21.8 0.12
Hispanic vs. other 3.4 0.5-‐21.5 0.19
Medical Comorbidity Index 0.8 0.4-‐1.6 0.58
Cogni1ve Func1oning (ARen1on) 1.1 1.0-‐1.2 0.04
Clinical Depression (BDI-‐II) 3.8 0.8-‐18.3 0.09
Life1me Psychiatric Diagnosis 0.04 0.003-‐0.5 0.01
Life<me Substance Use Diagnosis 0.2 0.01-‐2.1 0.17
Weiss et. al. XVIII Int’l AIDS Conference 2010
Mount Sinai & Johns Hopkins Real-‐world Telaprevir Triple Therapy
Martel-‐Laferrière et al. ICVH 2013 Mono-infected (N= 117); Co-infected (N=33)
N Mean Adherence
Standard Devia<on Range
Overall Adherence Baseline 57 93.65 12.02 40-‐100 Overall Adherence 12-‐weeks 53 93.59 12.17 40-‐100 Overall Adherence 24-‐weeks 48 95.85 6.92 68.5-‐100 Psychotropic Baseline 24 91.42 14.60 40-‐100 Psychotropic 12-‐weeks 22 92.73 15.18 50-‐100 Psychotropic 24-‐weeks 20 91.50 16.31 50-‐100 ARV Baseline 26 95.91 10.16 50-‐100 ARV 12-‐weeks 24 92.28 15.58 40-‐100 ARV 24-‐weeks 25 96.61 6.43 80-‐100 Other Baseline
45
94.25
11.55
40-‐100
Other 12-‐weeks 40 96.35 8.47 60-‐100 Other 24-‐weeks 35 96.78 8.50 65-‐100 PEG-‐INF Adherence 12-‐weeks 47 97.87 7.05 75-‐100 PEG-‐INF Adherence 24-‐weeks 31 98.39 8.98 50-‐100 RBV Adherence 12-‐weeks 47 96.70 7.42 70-‐100 RBV Adherence 24-‐weeks 31 97.26 7.73 60-‐100
Impact of hepatitis C treatment initiation on adherence to concomitant medications
HCV mono-infected (N=28; HIV/HCV co-infected N=29)
Pizzirusso et al. (2014) JANAC, 25, 23-31
Variable Es<mate SE Z-‐Value p-‐Value
Intercept 91.38889 2.01159 45.43112 <.00001
T12 3.46188 2.05858 1.68168 .09263
T24 4.16825 2.19109 1.90237 .05712
T12*HIV −7.31026 2.84854 −2.56632 .01028
T24*HIV −3.61084 2.96220 −1.21897 .22285
HIV 4.44559 2.82019 1.57635 .11495
Linear Regression on Overall Adherence
Pizzirusso et al. (2014) JANAC, 25, 23-31
Innova1ve Models of HCV Care
• Peer based model, D. Sylvestre (2007), J. Grebely (2010)
• Concurrent Group Treatment MMTP, Litwin (2009) • Collabora<ve, Mul<disciplinary, Integrated Care Model, B. Edlin
• Santa Clara Valley Homeless Clinic, C. Ho (2013)
Integrated care for high risk psychiatric and substance use disorder pa1ents with hepa11s C increases overall SVR rates:
Final results of a prospec1ve mul1site randomized trial
• Integrated Care (N=182); Usual Care (N=181) • IC – a mid-‐level mental health prac<<oner provided brief mental health interven<ons and case management according to a protocol
• Pa<ents had to be “high risk” based on screening for depression, alcohol use, and PTSD.
• More pa<ents in IC ini<ated an<viral therapy (31.9% vs. 18.8%, OR 2.036, p=0.005).
• 27% in each group received DAA triple therapy
Ho et al. # 2248 AASLD 2013
Ho et al. # 2248 AASLD 2013
• No guidelines for pre-‐treatment assessment of HCV treatment readiness
• No guidelines for on-‐treatment monitoring of HCV treatment adherence
Psychosocial Readiness Evalua<on and Prepara<on for hepa<<s C treatment (PREP-‐C)
• Background – Developed in response to lack of guidelines and screening tools to meet clinicians’ needs for assessing pa<ent’s psychosocial readiness to begin chronic HCV therapy
• Descrip<on – Clinical interview (30 – 45 minutes) – Assessment of 9 areas of psychosocial func<oning based on research findings and clinical experience
• Implementa<on – Piloted at Mount Sinai and revised – Web based version now available PrepC.org
Psychosocial Readiness
Alcohol and Substance Use
Medica1on Adherence
Self-‐ Efficacy
Social Support and Stability
Psychiatric Stability
Energy Level
Mo1va1on
Informa1on
Cogni1ve Func1oning
HCV Treatment Adherence
PrepC.org
Principles Guiding Development of PREP-‐C Assessment Tool
• Suitable to be administered by service providers from diverse disciplines
• Structured interview rather than self-‐report • Not to be used to “screen people out” of treatment but to
iden<fy areas which can be improved • Can be used with HCV mono-‐infected and HIV/HCV co-‐infected clients
• Provides opportunity for immediate interven<on and provision of resources
• Leads to plan for (referral to) further evalua<on and treatment
• Can be used in a diverse range of HCV treatment semngs
Goals of Using PREP-‐C • Iden<fy modifiable areas of psychosocial func<oning
which are predic<ve of HCV treatment adherence prior to HCV treatment ini<a<on in order to be able to create a treatment plan to improve func<oning in these areas prior to HCV treatment ini<a<on.
• Iden<fy non-‐modifiable areas of psychosocial func<oning which are predic<ve of HCV treatment adherence prior to HCV treatment ini<a<on in order to be able to plan for and take these factors into account during treatment.
• Level of support and resources available in treatment semng can be used to inform evalua<on of readiness.
Interven1on to Improve HCV Treatment Uptake and Adherence in HIV/HCV Coinfec1on
(MH099930)
• Phase I: Interven<on Development – FiWeen pa<ents randomly assigned to PREP-‐C interven<on (10 subjects) or acen<on control (5 subjects)
• Phase II: Pilot Randomized Clinical Trial – Sixty pa<ents to be randomly assigned to PREP-‐C interven<on (30 subjects) or acen<on control (30 subjects)
Week Training Module
1 (1) Administra<on of web-‐based PREP-‐C Interview
2 (2) HCV Psycho-‐Educa<on
3 (3) Mo<va<on and Behavioral Skills I
4 (4) Mo<va<on and Behavioral Skills II
Week Training Module
1 (1) Administra<on of web based SCID-‐II Interview
2 (2) HIV and ARV Therapy
3 (3) Adherence, Resistance and ARV Therapy
4 (4) Psychiatric and Medical Comorbid Condi<ons
Table 2: Attention Control Session Schedule
Table 1: PREP-C Intervention Session Schedule
52
Home My Status My Team
HepCure
Current Users
My Cure
HepCure Aims • To create a state-‐of-‐the-‐art innova<ve web applica<on (HepCure) that will engage with pa<ents to provide quality health care, expand the workforce, and enable improved outcomes
• HepCure is currently a partnership of: – An academic medical center (Icahn School of Medicine at Mount Sinai; P. Perumalswami, J. Weiss, A. Atreja)
– The New York State Department of Health AIDS Ins<tute (Colleen Flanigan, RN, MS, Director, Viral Hepa<<s Sec<on)
– The leading primary care associa<on in New York (Community Health Care Associa<on of New York State – CHCANYS)
HepCure • Engage pa1ents
– Pa<ents are primary stakeholders in their health – HepCure will be pa<ent-‐centered so as to improve adherence and quality of care
• Expand the workforce – Train primary care providers and physician extenders to screen, evaluate and treat pa<ents with HCV
• Enable improved outcomes • linking health-‐care providers from community prac<ces with
specialists experienced in trea<ng hepa<<s C – provide weekly case conferencing – create knowledge networks and training modules – real <me quality improvement dashboard
7:11 PM!iPhone
Home My Status My Team My Cure
Add Med
sofosbuvir
sofosbuvir
Appearance
Reminder
ON
Sound
Chimes
Continue >
7:11 PM!iPhone
Home My Status My Team My Cure 55
7:11 PM!iPhone
Home My Status My Team My Cure
Symptom Rating
Fatigue
General Body
Pain
Headaches
Irritability
Itching
Physical
Tiredness
7:11 PM!iPhone
Home My Status My Team My Cure 56
My Symptoms
Add custom symptom
HepCure Dashboard
Patients
In queue
On Rx
Cured
Population Amen, Jose
Resources Billing, Aaron
Communication
Carmen, Teresa
Help
Rogers, Edward
Community Health Brooklyn
Billing, Aaron MRN 123456
Patient
DOB 12/1/1954 Male, AA
Disease Profile
Genotype 1 A , No cirrhosis, Rx Naive
No co-infection, High viral load
Co-morbidities
No depression, no heart disease
Frequent sinusitis infections….
Insurance details
HepCure Dashboard
Patients
In queue
On Rx
Cured
Population Amen, Jose
Resources Billing, Aaron
Communication
Carmen, Teresa
Help
Rogers, Edward
Community Health Brooklyn
Rx Started 10/10/2013, Week 4
Treatment Details
Interferon + Ribavarin + Sofosbuvir
Treatment Response Viral Load
Adherence
Fatigue
HepCure Dashboard
Patients
Population
Amen, Jose
Resources
Billing, Aaron
Communication
Carmen, Teresa
Other
Rogers, Edwardo
Community Health Brooklyn
Waiting 100 On Treatment 50 Cured 20
TREATMENT NUMBERS (ALL CENTERS)
Center 5
Center 1
Center 2
Center 3
Center 4
Center 6
Center 7 Center 8
% HCV RNA TESTED % GENOTYPE TESTED
Grant Support
• Na1onal Ins1tute of Mental Health MH071177, MH099930 The content is solely the responsibility of the author and does not necessarily represent the official views of the Na<onal Ins<tute of Mental Health or the Na<onal Ins<tutes of Health.
• New York State Department of Health AIDS Ins1tute • Robin Hood Founda1on • New York State Health Founda1on • Boehringer Ingelheim Pharmaceu1cals, Inc. • Kadmon Pharmaceu1cals, LLC • Merck Sharp & Dohme Corp.
Cindy Aaronson Katy Amory Ashish Atreja Andrea Branch Norbert Bräu Michael Diefenbach Doug Dieterich Brian Edlin Daniel Fierer Colleen Flanigan Scott Friedman Donald Gardenier Jack Gorman Alyson Harty Nirah Johnson Livette Johnson Tony Kang Natalie Kil Katie Krauskopf Fabienne Laraque Jules Levin Carolyn Licht Susan Morgello Michael Mullen Michel Ng Ponni Perumalswami Eric Rude Keith Sigel Theresa Soriano Alicia Stivala Tracy Swan Juan Wisnivesky
Acknowledgments
Research Subjects and Patients
Contact Informa1on: Jeffrey J. Weiss, PhD, MS Associate Professor of Medicine Division of General Internal Medicine Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1087 New York, New York 10029
212-824-7575
www.PrepC.org