HCV in People who Inject Drugs (PWID)

Christian B. Ramers, MD, MPH, AAHIVS Assistant Medical Director – Research/Special Populations

Family Health Centers of San Diego

Disclosures

Speakers Bureau: Clinical Care Options (HIV), Janssen Therapeutics (HIV), ViiV (HIV), Gilead Sciences (HIV, HCV), AbbVie (HCV), Bristol-Myers Squibb (HCV)

Scientific Advisor: Gilead Sciences (HIV, HCV), Janssen Therapeutics (HCV), Bristol-Myers Squibb (HCV)

Grant/Contracted Support: California Dept of Public Health, UNM Project ECHO, CDC/HRSA, Pacific AETC, HealthHIV, California HIV Research Program (CHRP), Gilead Sciences

Employer: Family Health Centers of San Diego

Learning Objectives

At the end of this lecture, you will be able to:

• Describe the epidemiology of HCV in PWID

• Identify unique challenges in treating PWID

• Describe clinical trials including PWID

• Review Guidance on mgmt of HCV in PWID

– Injected once?

– Injects regularly?

– Injects occasionally?

– Last injected 35 years ago?

– On stable OST and no longer injects?

What do we mean by PWID?

Larney S, et al. Int J Drug Policy 2015;26:9507; Grebely J, Dore GJ. Antiviral Res 2014;104:62–72.

• NSP: needle/syringe programme;

• OST: opioid substitution therapy;

• PWID: people who inject drugs

Lifetime PWID

OST

NSP

Active PWID

Epidemiology

•3-4 million new infections/yr

•150-180 million infections worldwide

Estimated HCV Prevalence: Global

> 10% 2.5%-10%

1%-2.50%

Prevalence of infection

NA

World Health Organization 2008 (http://www.who.int/ith/es/index.html), Razavi et al AASLD 2013

Estimated HCV Prevalence in PWID Worldwide (millions)

Grebely J, Dore GJ. Antiviral Res 2014;104:62–72.

No evidence of injecting drug use

No eligible report (74 countries)

<40% (16 countries)

40–<60% (24 countries)

60–<80% (25 countries)

≥80% (12 countries) Global estimate: 10.0 million PWID (range 6.0–15.2)

Global prevalence: 67.0% of PWID

W Europe: 0.73 E Europe: 2.35

E/SE Asia: 2.64 South Asia: 0.35

S America: 1.02

N America: 1.67

Australia New Zealand: 0.10

Sub-Saharan Africa:† 0.80

Middle East N Africa: 0.06

Central America: 0.15

Prevalence of HCV in PWID

..

Estimated chronic HCV Prevalence: US

• NHANES1: 2.7-3.2 million

• Adjusted for homeless, institutionalized, prisoners, military2: 5-7 million

Denniston MM et al Ann Intern Med. 2014; 160:293-300, Chak E, et al. Liver Int. 2011;31:1090-1101,

• Declining Prevalence of HCV Ab (1.3%) AND HCV RNA (1.0%)

NHANES Survey: United States, 1988-1994 and 1999-2002

Prevalence of HCV Antibody, by Year of Birth

Armstrong GL, et al. Ann Intern Med. 2006;144:705-14.

Year of Birth

HC

V P

reva

len

ce

(%)

1910

1988–1994

1999–2002

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0

1920 1930 1940 1950 1960 1970 1980 1990

1945-1965

Hepatitis C Incidence in United States, 1982-2010

CDC MMWR 2010

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010

Nu

mb

er

of

Cases

Estimated New Infections

How is IDU contributing to HCV Epidemiology?

• Estimated 60% of prevalent HCV in US in current or former IDU’s1, 2

• Estimated 29,718 new infections in 2013

– 80% of incident HCV in PWID

• 3.8 Million have injected heroin at least once

– 425,000 have injected in the last year

• 289,000 actively injecting

• 64% of PWIDs are infected with HCV

1. Litwin AH, et al. Clin Infect Dis. 2005;40:S339-S345. 2. Grebely J, et al. Clin Infect Dis. 2013;57:1014-1020 3. CDC. MMWR. 2012;61:1-43 4. SAMHSA. National Survey on Drug Use and Health Report. September 4, 2014. 4. CDC. MMWR. 2015:64:1-7.

Increasing Incidence of HCV in Young PWID

MMWR. May 6, 2011:60; 17:537-541.

HCV testing at FHCSD – 12 month Results

Ramers C et al CROI abstract #661– Seattle, WA, Feb 24-27, 2015

Suryaprasad AG et al CID 2014, CDC, MMWR 2011, CDC MMWR 2015

Indiana HIV Outbreak - 2015

Brooks J – CROI 2016 – Boston, MA

Management Challenges in PWID

Very few PWID treated in IFN era

597

418

86 56

26 5

0

100

200

300

400

500

600

HCV antibody+ve

Aware oftreatment

Discussed withprovider

Agreed to starttreatment

Initiatedtreatment

Sustainedvirologicalresponse

Mehta SH, et al. J Community Health 2008;33:126–33.

n=237

Num

ber

of P

WID

<10% of PWID with HCV antibody positive were cured

PWID who receive HCV treatment ETHOS: 5 OST clinics, 2 CHCs, 1 aboriginal center in New South Wales, Australia, 2009–2012

Alavi M, et al. Clin Infect Dis 2013;57:S62–9.

387

236

191

84

0

100

200

300

400

500

600

Assessed by nurse Referred tospecialist

Attendedspecialist

appointment

Startedinterferon-based

treatment

Num

ber

of patie

nts

61% 49%

22%

100%

Reasons for Non-Engagement

Bamvita JM, et al. Hepat Res Treat 2014;2014:631481; ; Salvalaggio G, et al. SAGE Open 2013; doi:10.1177/2158244013509252. Harris, M. Hepatitis C testing & treatment for PWID: Barriers and Facilitators.

Alcohol consumption

Homeless or living in temporary accommodation

(shelters, prison)

Poorly educated (secondary education or less)

Poor quality of life

Limited access to healthcare

Use of multiple substances

“I am treated as a criminal and this makes it hard to take care of my health”

“There are no friendly healthcare services near where I live”

“I cannot get opioid substitution therapy/syringes because it is illegal”

“I would like to give up drugs, but I cannot get help”

“Healthcare workers do not trust me, as if I just want drugs”

“Without clean needles and syringes, I have to share”

Pt-reported Barriers in OST & NSPs

Feller S, et al. AASLD 2013; Oral #274.

Fear of judgement by doctor

0

20

40

60

80

100

No insurance

Can’t afford to pay

Can’t afford

transportation

Treatment will make me sick

Fear of liver

biopsy

Feel fine without

treatment

Patients

(%

)

Self-reported barriers to care among HCV-positive PWID (n=117)*

Reasons for non-referral/non-treatment in a testing/linkage program in Denver

0 10 20 30 40 50 60

Muething L, et al. ID Week 2015, Poster #1029.

•

• Individuals born 1945–1965 were screened for HCV and HCV evaluation, and treatment courses were followed prospectively from January 2013–March 2015. PWID: people who inject drugs

Reaso

ns n

ot

refe

rred

t

o H

CV

care

Reaso

ns n

ot

treate

d f

or

HC

V

Mental illness

Referral declined

Lost to follow-up

Medical disease

Not documented

Substance abuse

Mental illness

Substance abuse

Medical disease

Work on-going

Lost to follow-up

Not advanced liver disease

11

14

14

29

46

55

4

4

8

9

23

28

Number of HCV-infected individuals

• Most common reasons: substance abuse and co-morbid medical disease.

Clinical Trials of HCV treatment in PWID

Retrospective analysis: ION-1, -2, -3: patients on stable OST

• No differences between OST and non-OST participants:

– Overall SVR12 (94% vs. 97%, p=0.29)

– Adherence to LDV/SOF ≥80% (94% vs. 96%, p=0.33)

– Proportion with AEs (89% vs. 80%, p=0.07)

• No cases of HCV reinfection were observed up to SVR24

Jacobson I, et al. AASLD 2014; Poster #1945.

8 weeks 12 weeks 24 weeks 8 weeks 12 weeks 24 weeks

LDV/SOF+RBV LDV/SOF

SV

R 1

2 (

%)

0

10

20

30

40

50

60

70

80

90

100

Patients not receiving OST Patients receiving OST

94 100 97 94 99 91

93 100

97 91 99 100

196/ 209

6/6 492/ 508

29/31 311/ 315

10/11 195/ 210

6/6 308/ 317

10/11 320/ 323

5/5

. IFN: interferon; LDV: ledipasvir; OST: opioid substitution therapy;

SOF: sofosbuvir; RBV: ribavirin; PWID: people who inject drugs

High SVR12 for pts on OST with OMV/PTV/RTV + DSV + RBV

Lalezari J, et al. J Hepatol 2015;63:364–9.

97 97 97

0

20

40

60

80

100

37/38 37/38 37/38

EOT SVR4 SVR12

Virolo

gic

al r

esponse (

%)

Phase 2, open-label, single arm study of OMV/PTV/RTV + DSV for 12 weeks in GT 1 adult patients on stable OST with methadone or buprenorphine (N=38)

Grazoprevir/Elbasvir x 12 weeks in pts on OST (C-EDGE CO-STAR)

92 94 93 92

20

0

20

40

60

80

100

All GT GT 1a GT 1b GT 4 GT 6

Dore G, et al. AASLD 2015 Oral #49.

SVR

12

(%

)

Phase 3, randomised, double-blind study in PWID on OST with GT 1, 4 or 6 (n=201)

17 patients did not achieve an SVR

– 7 cases of relapse

– 5 cases of re-infections

– 5 patients were lost to follow-up or discontinued due to events unrelated to treatment failure

184/201 144/154 28/30 11/12 1/5

ELB/GRZ x 12 weeks in pts on OST – C-EDGE CO-STAR: Adherence

100 99 97

0

20

40

60

80

100

Dore G, et al. AASLD 2015 Oral #49.

>80% (>67 doses)

>90% (>76 doses)

>95% (>79 doses)

Adhere

nce (

%)

Phase 3, randomised, double-blind study in PWID on OST with GT 1, 4 or 6

Number of missed doses

Number (%) patients

0 153 (76.9)

1 23 (11.6)

2 8 (4.0)

3 8 (4.0)

4 1 (0.5)

≥5 6 (3.0)

Adherence Missed doses

99% (199/201) patients completed 12 weeks of treatment with grazoprevir/elbasvir

Majority of patients (97%) missed 3 doses or fewer

Around 60% patients tested positive for illicit drug use during the study

199/199 197/199 192/199

High SVR12 for PWID in Community setting

Norton BL et al CROI 2016

121 consecutive patients from urban FQHC in the Bronx

HCV Care Coordinator responsible for scheduling, reminder calls, prior authorizations

Outcomes compared between People who use drugs (Opiate substitution therapy or positive Urine tox screens)

HCV Re-infection rates in PWID

Pooled estimate of HCV reinfection risk for PWIDs1:

2.4 (95% CI 0.9–6.1) per 100 person-years

• Reinfection rates among PWIDs may be higher:

• In communities with high HCV prevalence2

• For young PWIDs3-5

• For active injection drug users3-5

Reinfection Rates Are Low Among PWID (‘ever’ injectors)

Reinfection Rates Among Persons Who Ever Injected Drugs Per 100 Person-Years2

Australia 4.70

Germany 3.94

Netherlands 0.76

USA 2.63

Norway 0.80

Canada 3.20

1. Aspinall EJ, et al. Clin Infect Dis. 2013;57(suppl 2):s80-s89. 2. Grady BP, et al. Clin Infect Dis. 2013;57(suppl 2):s105-s110. 3. Aitken CK, et al. Hepatology. 2008;48:1746-1752. 4. Micallef JM, et al. J Viral Hepat. 2007;14:413-418. 5. Page K, et al. J Infect Dis. 2009;200:1216-1226

Risk of HCV re-infection in low and high risk groups and HIV/HCV co-infection

Hill A, et al. CROI 2015, Abstract #654.

Meta-analysis of 66 studies in 11,071 patients

Low risk 43 studies; N=9,419

FU=4.1±2.1 years

High risk (PWID/prisoners) 16 studies; N=819

FU=2.9±1.6 years

HIV/HCV co-infected 7 studies; N=833

FU=3.1±1.2 years

0

2

4

6

8

10

Low risk High risk HIV/HCV co-infected

Rec

urr

ence

rat

e/

10

0 p

atie

nt

year

s

0.23 (95%CI 0.18–0.28)

2.80 (95%CI 2.06–3.71)

4.78 (95%CI 3.97–5.71)

Practical Considerations

HCV Can Be Managed in PWIDs Across the Spectrum

Former Injectors

Opioid Agonist Therapy

Active Injectors

HCV treatment outcomes

improved among those treated for

opioid addiction compared to

untreated individuals2

• Occasional drug use does not

impact adherence, treatment

completion, or treatment efficacy1

• Frequent drug use (daily/

every other day) does1

Successful HCV outcomes are more

likely to be achieved if PWIDs are

stabilized for addiction and then

undergo HCV therapy3

1. Robaeys G, et al. Clin Infect Dis. 2013;57(suppl 2):s129-s137.

2. Dimova RB, et al. Clin Infect Dis. 2013;56:806-816.

3. Zeremski M, et al. World J Gastroenterol. 2013;19:7846-7851.

Risk of HCV Transmission and Progression in PWIDs

Grebely J, et al. Clin Infect Dis. 2013;57:1014-1020. .

• Lower risk of

advanced liver disease1

• Higher risk of HCV transmission

due to the propensity of young/new

PWIDs to share needles and

syringes

• Moderate risk of advanced liver

disease1

• Moderate risk of

HCV transmission1

• Higher risk of

advanced liver disease1

• Lower risk of

HCV transmission1

15 25 35 45 55 65

Years of age

Individual Level1 Risk of liver-related morbidity

and mortality

Population Level1 Risk of HCV transmission

Highest prevalence of PWIDs2

Summary

• PWIDs are disproportionately affected by HCV

– 60% of prevalent and 80% incident infections in US

• Ample evidence of increasing HCV incidence among young people using opiates

• Growing body of clinical trials and ‘real world’ studies showing comparable SVR rates

• Professional societies recommend comprehensive approach involving Opiate Substitution therapy, case management, HCV treatment

Questions?

Extra Slides: Drug-drug interactions

Potential for drug interactions between OST and DAAs

Drug interaction charts. Available at: www.hep-druginteractions.org

DCV LDV/SOF OMV/PTV/ RTV + DSV

SMV SOF

Buprenorphine

Methadone

No clinically significant interaction expected

Potential interaction – may require close monitoring, alteration of drug dosage or timing of administration

Potential for drug interactions between antidepressants, antipsychotics and DAAs

Adapted from EASL. J Hepatol 2015;63:199–236.

DCV LDV/SOF OMV/PTV/ RTV + DSV

SMV SOF

Antidepressants

Amitriptyline

Sertraline

Trazodone

Venlafaxine

Antipsychotics

Aripiprazole

Chlorpromazine

Clozapine

Flupentixol

Haloperidol

Olanzapine

Quetiapine

Risperidone

No clinically significant interaction expected Potential interaction Do not co-administer

Extra Slides: Published Guidelines

2015 INHSU recommendations on management of HCV among PWID

Grebely J, et al. Int J Drug Policy 2015;26:1028–38.

Prevention • Access to OST and sterile injecting equipment as part of widespread

harm reduction programmes

Screening • Annual screening via anti-HCV with RNA confirmation of positive tests • Non-invasive liver fibrosis assessment should be offered to enhance screening

Assessment • Pre-assessment should include HCV education and evaluation of social situation • Models of integrated HCV care to increase linkage between addiction and HCV services

to support successful pre-assessment

Treatment • SOF, LDV/SOF, OMV/PTV/RTV + DSV ± RBV, DCV or SMV are suitable regimens depending

on local availability and patients’ disease characteristics

Management • Individualised and delivered in a multidisciplinary team • Access to harm reduction programmes

Prisoners • Screening and assessment should be offered • Treatment is feasible and should be offered

EASL Recommendations 2015

• PWID should be routinely tested for HCV antibodies and, if negative, every 6–12 months (B1)

• Provided with clean drug injecting equipment and access to OST as part of widespread comprehensive harm reduction programmes, including in prisons (B1)

• Pre-therapeutic assessment should include evaluation of housing, education, cultural issues, social functioning and support, finances, nutrition, and drug and alcohol use. PWID should be linked into social support services and peer support if available (A1)

• A history of IDU and recent drug use at treatment initiation are not associated with reduced SVR and decisions to treat must be made on a case-by-case basis (B1)

• The anti-HCV regimens that can be used in PWID are the same as in non-PWID. No dose adjustment for methadone or buprenorphine is required but monitoring for opioid toxicity or withdrawal should be undertaken. More data are needed for daclatasvir (B1)

EASL. J Hepatol 2015;63:199–236.

AASLD/IDSA Guidelines 2015

• PWID should receive treatment because of the elevated risk of HCV transmission (IIa, Level C)

• Annual HCV testing is recommended for PWID and for HIV seropositive MSM (Class IIA, Level C)

• Adherence and efficacy rates are comparable to those of patients who do not inject drugs

• The rate of reinfection in PWID who are treated is lower (2.4/100 py) than that of incident HCV in this population (6.1-27.2/100 py)

AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: www.hcvguidelines.org/full-report-view (accessed August 2015).