micro elimination of hepatitisc in people who usedrugs · 2021. 4. 24. · disclosure statement for...
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Micro‐elimination of Hepatitis C in People Who UseDrugs
Arthur Y. Kim,MDDivision of Infectious Diseases
Massachusetts GeneralHospital Harvard Medical School
KYAETCAnnual HIV/HCV Conference
April 23, 2021
Disclosure Statement for ArthurKim
Grant/research support to institution: No relevant disclosures in past 12 months(Updated 4/14/21)
I will discuss the following off-label use in this presentation: Treatment of acute HCV
Funding:• National Institutes of Health (National Institute of Allergy and Infectious Diseases, National Institute of Drug Abuse, National Institute of Aging)
• PCORI
Objectives and outline
• Discuss challenges that face patients, providers, and public health in reducing the burden of HCV for persons who use drugs
• Review potential solutions to preventing and treating HCV in PWID
• Outline:
• Case and brief review of HCV in a person who inject drugs
• Discuss persistent challenges and potential solutions
What does “Elimination” mean?
• Estimated 71 million people living with chronic HCV infection worldwide, liver disease burden resulting in approximately 400,000 deaths per year from liver failure and liver cancer.
• In the U.S., estimated 3 million persons infected, 2nd leading single infectious cause of death
• Goal is “elimination as a public health problem” by 2030
• The World Health Organization (WHO) has set 2030 global elimination targets for HCV:
• 80% of those eligible treated
• 90% reduction in incidence of new infections
• 65% reduction in liver-related mortality
WHO, NASEM National Strategy for the Elimination of Hepatitis B and C
What does “micro‐elimination” for PWIDmean?
Figure credit David Thomas, Johns Hopkins; Hajarizadeh et al. Nature Rev Gastroenterol Hepatol 2013; Grebely and Dore Antiviral Res 2014
PWID: 60% of existing infections and the up to 80% of new transmissions in many
countries
PWID are a priority group for elimination goals
A case
• 18 y/o woman presents to a psychiatric hospital for inpatient detoxification from opioids, post-traumatic stress disorder
• Negative testing 6 months earlier
• Transitioned 2.5 months ago to intravenous use from snorting
• Clean needles/syringes each use, but shared with boyfriend, who told her he is HCV negative
• She is concerned for HCV and requests RNA testing after research on internet
18 y/o woman presents to a psychiatric hospital for detoxification from opioids
• Testing shows: ALT 16, HCV Ab negative, HCV RNA negative
• HIV, syphilis negative, HBSAg negative, HBSAb negative
• Boyfriend suffered torn ACL playing football 1.5 years earlier
• Lost commitment for college scholarship
• Progressed from oral opioid use to snorted heroin to injected heroin
• She defers college (accepted to prestigious art school)
• She read about incubation times on the internet and requests repeat labs 2.5 weeks later
• HCV Ab negative
• ALT 435
• HCV RNA 639,000 IU/mL
Diagnosis: Acute HCV
Questions that arise from the case
• What is the natural history of infection?
• If she doesn’t clear, why should we treat her early?
• What are special considerations as a young woman with HCV?
• What barriers to receipt of HCV care would she (and her boyfriend) face?
• How do we prevent re-infection?
Natural history of HCV
Cirrhosis
Liver failure HCC
Death
Acute infection
Chronic infection
Viral clearance
~80%
~20%
~20%
Stable or slowly
progressive
Alcohol Coinfections (HIV, HBV)
Weight gain / NASH
Patterns of viremia following acute HCV infection
• INC3: The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts Study - n=623 incident cases
41% plateau without control
27% partial control
32% spontaneously clear
Hajarizadeh et al. PLoS One 2015
Women of childbearing age are at increased risk for HCV
• National birth data indicate rising HCV maternal prevalence
• AASLD/IDSA/CDC recommend screening of pregnant women
• Sparse data regarding treatment during pregnancy but women of childbearing age can be treated before or between pregnancies
Rossi et al. Obstet Gynecol 2020
Major challenges to eliminating HCV
Silence
• The virus spreads silently, causes liver fibrosis silently
• The majority of persons with HCV don’t know it
• Public health surveillance varies
• Concerns regarding HCV are often muted by other pressing issues
• There are few vocal advocates
Substances Social/Structural
• People who use drugs face stigma
• Harm reduction is variably available
• Other social determinants frequent,e.g. incarceration, homelessness
• Care and services are often unavailable, inaccessible, or fragmented
• Provider shortage / provider-level concerns (e.g. adherence)
• Policies that exclude patients from treatment
Incidence, prevalence and sustaining an epidemic
Rising opiate use
Barriers to care, access restrictions and cost of treatment
Lack of surveillance
Lack of prevention services
Asymptomatic infection Unknown serostatus
Potential solutions ‐ public health appraoches
Public Health
• Surveillance and monitoring
• Case-finding and care coordination
• Increase screening and treatment capacity
• Increase public awarenessHall et al. Hepatology 2021
Potential solutions
PreventionPublic Health
• Surveillance and monitoring
• Case-finding and care coordination
• Increase screening and treatment capacity
• Increase public awareness
• Testing
• Vaccine
• Harm reduction
• Treatment as prevention
“Toolbox” for HCV prevention for PWID
•HCV testing and counseling
•Drug treatment•Reducing transmission from positive partners
•Vaccine
•Change injecting behavior
•Clean injecting equipment• Syringes/needles• “extras”
•Safe injecting locations
•Viral titer testing•Antiviral treatment
Adapted from Kim Page, UNM
Randomized trial of a vaccine to prevent chronic HCV
Enrolled 548 high-risk individuals (based on recent injection exposures)
Immunogenic but similar rate of incident and chronic infection between groups Vector based on 1b virus (1a and 3 most likely transmitted) and nonstructural proteins (envelope = target of nAbs)
Page et al. NEJM 2021
Likelihood of HCV infection: duration of IDU
Hagan et al. Am J Epidemiol 2008; 167:1099
Depends on context: much higher in areas without services for PWID
HCV is NOT inevitableYears after initating injection drugs
Opioid substitution therapy and SSPs for preventing hepatitis C transmission in people who inject drugs
Cochrane Database of Systematic Reviews 2017; https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012021.pub2/full
OAT associated with 50% incidence reduction
When added to access to high-coverage needle
syringe programs, 75% reduction in HCV incidence
Rates of maternal HCV declined after establishment of SSP in Scioto County,OH
Rossi et al. Am J Perinatol 2020
% Change in Maternal HCV Prevalence
-300
0
300
600
900
1200
Scioto Adams Jackson Lawrence Pike Gallia Meigs
109
1,020
-29
7124
-62
12
597
466
Vinton Brown
4147
425442448
218
648
346
137
2006-20112012-2015
Incidence among PWID differs in Amsterdam versus two sites in U.S.
0
10
20
30
40
50
60
70
80
1986,1990 1991,1993 2003,2005 2006,2011
Incide
nce (per
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y)
1997,1999
Enrollment Year
Amsterdam
0
10
20
30
40
50
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70
80
1997,1999 2000,2002 2006,2008 2009,2011
Incide
cne (per
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y)
2003,2005Enrollment Year
Bal7more
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50
40
30
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2000+2002 2009+2011
Incide
nce (per10
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2003+2005Enrollment
2006+2008Year
San Francisco
Morris M et al. Clin Infect Dis 2017
Amsterdam Baltimore
San FranciscoIn
cide
nce
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py)
2000-2002 2003-2005 2006-2008 2009-2011
1997-1999 2000-2002 2003-2005 2006-2008 2009-20111986-1990
1991-1993
1994-1996
1994,1996 2000,2002
1997-1999
2000-2002
2003-2005
2006-2011
HCV care is not only about DAAs
22
Parenteral (Harm Reduction) Safe tattoos
Sexual (esp. if HIV+) Household (Razors/Toothbrushes)
HIV (PREP)STDs (screening, counseling)
Bacterial infections
Obesity Tobacco
Cardiovascular Prevention Naloxone for overdose
Substance use Psychiatric disorders
HousingSupport system
Hepatitis A Hepatitis B Influenza
Pneumococcal (F3+)
Diagnose advanced fibrosis (exam, noninvasive means)
Diagnose HCCCounsel alcohol reduction
Discuss herbals/hepatotoxicity
ACTG 5360 MINMONStudyMinimal monitoring ‐ “Keep it simple”
Exclusions: pregnancy, HBsAg+, decompensated 31% history of PWID, 6% recently injecting
Solomon et al. AASLD 2020
SIMPLIFY: recent drug use including those not onOST
Grebely et al. Lancet Gastroenterol Hepatol 2018
Should we worry about adherence of people who inject drugs ‐ SIMPLIFY
Grebely et al. Lancet Gastroenterol Hepatol 2018
All 4 of these patients achieved SVR!
• All patients follow an individualized treatment plan to facilitate adherence; and receive one of three color coded levels of treatment support.
• Green: minimal intervention and permitted to start oral DAA therapy on their own.
• Yellow: moderate intensity support including a mandated nurse visit to initiate DAAs with onsite delivery of DAA .
• Red: significant support including a mandated nurse start visit, onsite delivery of DAA and frequent visits ; up to weekly with their nurse, pharmacist or HCV provider.
• All patients receive contact from the care team within the first week and at least monthly during the course of HCV therapy.
The Hopkins Infectious DiseaseApproach
Falade-Nwulia O, et al. CROI 2018
De‐restricting access to DAAs for PWID in Iceland resulted in lower prevalence
Thorarinn Tyrfingsson et al. EASL 2018
Address social networks
Hellard et al Hepatology 2014: Hellard et al JECH 2016; Hochstatter et al. Emerg Infect Dis 2021
ask patients to “bring their
friends”
Injecting networks in MelbourneRural Wisconsin networks
shown by phylogenetic analysis
The Outcome of theCase
• 18 y/o woman with acute HCV, treated in the chronic phase
• Continued monthly naloxone injections
• Brief periods of homelessness
• Re-immunized for HBV
• Received 12 weeks of sofosbuvir/velpatasvir and achieved SVR
• Regained scholarship to art school
• Boyfriend also completed treatment, attending college, on buprenorphine/naloxone
• No re-infection, 3 years after
Potential solutions
PreventionPublic Health People and Policy
• Surveillance and monitoring
• Case-finding and care coordination
• Increase screening and treatment capacity
• Increase public awareness
• Vaccine
• Harm reduction
• Treatment as prevention
• Engage peers
• Expand provider capacity
• Adapt or build structures
• Reduce stigma
• Advocate for change
ECHO models equip local providers to expand access to specialty care
Andrew Aronsohn and telemedicine team, University of Chicago Institute for Translational Medicine (ITM) Photography
Models that bring services to themarginalized
▪▪▪▪▪▪
Social marketing campaign Door-to-door outreachRapid screening via mobile medical unit Assistance with insurance enrollment Facilitate referrals from PCPsFacilitate linkage to specialist
▪ Do One Thing: community-based HCV screening and linkage program in medically underserved Philadelphia neighborhood with high HCV rate
Trooskin SB, et al. J Gen Intern Med. 2015;30:950-957.
▪ DeLIVER Care: Mobile shuttle in San Francisco
▪▪▪▪▪▪
Repurposed UCSF Shuttle repurposedRapid screening via Oraquick (20 min)VenipunctureFibrosis staging - Fibroscan mini-deviceCounselingFacilitate linkage to specialist for Tx
Boston Healthcare for the Homeless
Beiser ME et al. Int J Drug Policy 2019
• BHCHP serves ~11,000 homeless and marginally-housed patients/year
• 23% HCV• 60% any SUD• 48% behavioral health dx and SUD
• HCV Program: PCPs with HCV expertise• RN and care coordinator• Low-threshold policy• High-touch adherence support• Acceptance of less than perfection
• Adapted from HIV care coordination programs
• Health education, motivational interviewing, coaching
• Goal: treatment adherence and increased self-sufficiency; goes beyond just getting someone to be in care, purpose is to also increaseself-efficacy and self-management
Patient / Peer Navigation
https://hepfree.nyc/resources/training-technical-assistance/nyc-hep-c-toolkit/ https://www.nastad.org/hepatitis-navigation-toolkit
Real‐World DAAOutcomesAmong PWID:The Hepatitis C Real Options (HERO) Study
SOF, sofosbuvir; VEL, velpatasvir.
• National study: 25 sites in 8 states• Active PWID who have injected drugs
within 12 weeks of study entry– Treatment: SOF/VEL for 12 weeks
• On-site HCV treatment– Community-based clinics– Opioid treatment programs
• Stakeholders– National advocacy and medical organizations (eg, HRC, NVHR, AATOD,
NATAP, HEP, HCMSG, Coalition for Global Hepatitis Elimination), government (eg, CDC, state and county DOH), clinicians, patients, and industry
Litwin et al. AASLD 2020
HERO StudyDesign
v
mDOT
RandomizationPatient Navigation
Tx Initiation
Tx Initiation
EOT
EOT SVR 12
SVR 12
Consent Baseline Week 0
Up to 12 weeks to initiate treatment
Week 12
12 weeks sof/vel
Week 24
Week 120
Monthly follow up
Quarterly follow up
Litwin et al. AASLD 2020
HERO Study Flow
Allocated to mDOT
n=376
Allocated to PN
n=379
Initiated HCV treatment with mDOT
n=306
Initiated HCV treatment with PNn=317
SVR available
n=248
SVR available
n=256
Analysis populations
• ITT (n=376)
• mITT (n=306)
• PP (n=248)
Analysis populations
• ITT (n=379)
• mITT (n=317)
• PP (n=254)
Randomized
n=755
Assessed for eligibility
n=1891
Excluded (n=1136)• No HCV VL test (n=458)• Drug injection ˃12 weeks (n=385)• Declined to participate (n=213)• Missed the 12-week eligibility window (n=102)• Previous DAA treatment (n=74)• HCV VL undetectable (n=71)• Never injected drugs (n=62)• Other (n=128)
Allocation
Initiation
Follow‐up (SVR)
Analyses
Enrollment
• Intention‐to‐treat (ITT): all randomized participants
•Modified Intention‐to‐treat (mITT): randomized and initiated treatment
•Per‐protocol (PP): randomized, initiated treatment, no cross over and had SVR12 outcomeLitwin et al. AASLD 2020
HERO Participant Characteristics
Characteristic, n (%)mDOT N=376
PN N=379
Total N=755
GenderFemale MaleTransgender or gender nonconforming
109 (29.0)262 (69.7)5 (1.3)
109 (28.8)266 (70.4)3 (0.8)
218 (28.9)528 (70.0)8 (1.1)
Age<40 years≥40 years
165 (43.8)211 (56.2)
169 (44.6)210 (55.4)
334 (44.2)421 (55.8)
RaceWhiteBlack/African American Other
226 (62.4)66 (18.2)70 (19.3)
250 (67.9)37 (10.1)81 (22.0)
476 (65.2)103 (14.1)151 (20.7)
Latino/Hispanic ethnicity 79 (21.0) 84 (22.2) 163 (21.6)Marital/cohabitation status
Single/separated/divorced/widowed Married/cohabitation
323 (87.5)46 (12.5)
325 (88.1)44 (11.9)
648 (87.8)90 (12.2)
Living situationStable Unstable
177 (48.0)192 (52.0)
162 (43.9)207 (56.1)
339 (45.9)399 (54.1)
Availability of transportationYesMaybe or no
149 (40.3)221 (59.7)
153 (41.6)215(58.4)
302 (40.9)436 (59.1)
Employed with a regular job or informal workYes No
135 (36.7)233 (63.3)
122 (33.1)247 (66.9)
257 (34.9)480 (65.1)
Genotype (GT)GT1GT2GT3
185 (74.0)22 (8.8)39 (15.6)
183 (69.3)23 (8.7)55 (20.8)
368 (71.6)45 (8.8)94 (18.3)
Characteristic, n (%)mDOT N=376
PN N=379
Total N=755
Clinical settingOpioid treatment program Community‐based clinic
153 (40.7)223 (59.3)
159 (42.0)220 (58.0)
312 (41.3)443 (58.7)
Any medication for OUD in the past 3 monthsBuprenorphine Methadone
59 (16.5)194 (54.2)
48 (13.4)205 (57.4)
107 (15.0)399 (55.8)
PHQ‐9 severityMild‐moderate (≤14) Moderately severe/severe (>14)
270 (75.5)88 (24.6)
174 (76.8)83 (23.2)
544 (76.1)171 (23.9)
HIV co‐infection 52 (20.3) 50 (18.7) 102 (19.5)
Alcohol misuse (AUDIT‐C) 112 (31.7) 117 (33.1) 229 (32.4)
Last drug injection (within 3 months of screening)0‐4 weeks5‐12 weeks
281 (74.7)95 (25.3)
291 (77.0)87 (23.0)
572 (75.9)182 (24.1)
Number of drug injections/day≤2 per>2 per
182 (53.5)158 (46.5)
173 (50.9)167 (49.1)
355 (52.2)325 (47.8)
Urine drug screen results at baseline visitAny drug Amphetamine Methamphetamine Benzodiazepine CocaineOpiate Oxycodone
292 (86.4)97 (28.7)106 (31.4)175 (51.8)148 (43.8)180 (53.3)94 (27.8)
284 (82.6)96 (27.9)112 (32.6)183 (53.2)139 (40.5)170 (49.4)88 (25.6)
576 (84.5)193 (28.3)218 (32.0)358 (52.5)287 (42.1)350 (51.3)182 (26.7)
SVR in the HERO trial
P=0.61P=0.35
P=0.44
Litwin et al. AASLD 2020; note results are updated as of April 2021 after data cleaning
• Lower SVR if:• age < 40•unstable housing•buprenorphine (compared to methadone)
•baseline injecting > 2x day• last drug injection 0‐4 weeks (compared to 5‐12 weeks)
CascadeTowardsCure in the HEROTrial
P=0.414
P=0.392 P=0.542
DOT 81.4%PN 83.6%
DOT 82.0%PN 83.3%
DOT 83.3%PN 81.8%
Litwin et al. AASLD 2020; note results are updated as of April 2021 after data cleaning
Conclusions: HERO
• In this pragmatic randomized trial of patient-centered models of HCV treatment in active PWID– SVR rates were similar with mDOT and PN models (PP 88.7% and 90.6%)– > 80% of enrolled PWID initiated and completed treatment– Among active PWID undergoing treatment for HCV infection within opioid treatment
programs, adherence was higher with mDOT vs. PN– Increased adherence and treatment duration as well as treatment completion were
significantly associated with SVR– Limitations: study sites located in urban areas - two sites served rural participants– Phase 2: examine rates of reinfection over a 3-year period
• U.S.-based evidence that “real-world” treatment in PWID is effective; room to optimize
Attacking the HCV epidemic
Prevent / reduce harm Cure as prevention Develop a vaccine
Increase / Improve testing
Improve capacity, develop models of care and provide access to curative
treatment
Increase provider awareness Provide access to staging
Promote liver health
Enhance surveillance
Summary
Substances
Social/Structural
Prevention
Public Health
People and Policy
Silence• HCV has a silent natural history but leading cause of
liver disease and death
• HCV is spreading, driven by substance use
• Social / structural barriers threaten elimination of HCV
• Safe, effective therapies provide hope for cure of individuals and populations
• HCV is preventable through harm reduction, OAT
• To eliminate HCV as a public health problem we must:
• Screen populations at risk
• Meet patients where they are
• Build infrastructure to faciliate HCV treatment
• Effect policy change
• ID specialists are uniquely poised to be part of this!
Advocacy
Acknowledgements
The HERO Research Group includes the primary investigator (PI) and co-investigators from each of the 9 sites, PIs from the CDC and the NYC DOH, statisticians and key staff (eg, project directors, patient representatives), and key stakeholders.The HERO study sites are Clemson University and Prisma Health, Albert Einstein College of Medicine/Montefiore Medical Center, University of Rhode Island, Johns Hopkins Bloomberg School of Public Health, Massachusetts General Hospital, University of California–San Francisco, University of New Mexico, University of Washington, and West Virginia University. Research reported in this presentation was supported through Patient-Centered Outcomes Research Institute (PCORI) Award HPC‐1503‐28122 with additional support from Gilead Sciences, Quest Diagnostics,Monogram Biosciences,and OraSureTechnologies.The opinions presented in this work are solely the responsibility of the authors and do not necessarily represent the views of PCORI, its board of governors, or its methodology committee.
Alain H. Litwin, MD, MS, MPH Judith Feinberg, MDArthur Y. Kim,MDPaula J. Lum, MD, MPH Shruti H. Mehta, PhD, MPH Brianna L. Norton, DO, MPH Kimberly A. Page, PhD,MPH Lynn E. Taylor, MD, FAASLD Judith I. Tsui, MD, MPH