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.

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1997-1999 2000-2002 2003-2005 2006-2008 2009-20111986-1990

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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