The Challenge of Addiction and Hepatitis C

Diana Sylvestre, MDUniversity of CA, San FranciscoOASIS

HCV Prevalence by Selected GroupsUnited States

0.3%

1%

2%

3.5%

6%

10%

30%

79%

87%

0 10 20 30 40 50 60 70 80 90 100

Hemophilia

Injection drug users

Surgeons, PSWs*

Hemodialysis

Average Percent Anti-HCV Positive

Gen population adults

Military personnel

STD clients

Pregnant women

* PSWs (personal-service workers) are individuals whose occupations involve close personal contact with clients (e.g., hairdressers, barbers, estheticians, cosmetologists, manicurists, pedicurists, massage therapists).Adapted from CDC Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset.

HIV patients

Injecting Drug Use and HCV Transmission

• Highly efficient– Contamination of drug paraphernalia, not

just needles and syringes• Rapidly acquired after initiation

– 30% prevalence after 3 years– >50% prevalence after 5 years

• Four times more common than HIV

Adapted from CDC Hepatitis Slide Kit.

Relative Importance of Risk Factors for Hepatitis C

Remote (>15 yrs ago) Recent (<15 yrs ago)

Transfusion

Sexual

Other*

Unknown

TransfusionInjection Drug Use

Unknown

Other*Sexual

Injection Drug Use

* Nosocomial, occupational, perinatalAdapted from CDC Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset

“Drug Users” are heterogeneous

Cannabis

MethamphetamineCocaineHeroin

Regular useBinge use

Polysubstance useIntermittent useInjection

Intra-nasal Oral

The evidence for addiction as a brain disease

Dopamine release in the Nucleus Accumbens is a common characteristic of virtually every drug of abuse.

Koob, Trends in Pharm Sci, ,1992

DMT VTA

LC

Frontal Cx

N. Acc

Hippo

AMG

Treatment options for depression

• Tricyclics (TCAs)– Amitriptyline, imipramine, nortriptyline, etc.

• Monoamine oxidase inhibitors (MAOIs)– Phenelzine, tranylcypromine, isocarboxazid, etc.

• Selective serotonin reuptake inhibitors (SSRIs)– Fluoxetine, sertraline, paroxetine, fluvoxamine,

citalopram, etc.

• Serotonin antagonists– Trazodone, nefazodone

• Other agents – Bupropion, venlafaxine, mirtazapine, reboxetine, etc.

Treatment options for addiction

• Alcohol– Disulfiram, acamprosate, naltrexone

• Opiate– Methadone, buprenorphine, naltrexone

• Stimulants– ?

Heroin-associated Mortality

Hser, Y. I., et al. (2001) Arch Gen Psychiatry, 58, 503-8.

Progression of Liver Fibrosis Among IDUs With Chronic HCV

• 119 prospectively followed IDUs

• Demographics– 96% were African American– 97% HCV genotype 1– 27% HIV-infected– Median age 42 years.

• After 4.2 years median follow-up 21% had progression of fibrosis

Wilson LE, et al. Hepatology. 2006 Apr;43(4):788-95.

Significant Fibrosis

9.3%

Insignificant Fibrosis

90.7%

Significant fibrosis was defined as modified Ishak score 3 or greater,

and progression of fibrosis was defined as an increase 2 or more units or clinical evidence of end-

stage liver disease.

Significant fibrosis at first biopsy:

“HCV therapy has been successful even when the patients have not abstained from continued drug or alcohol use... Thus, it is recommended that treatment of active injection drug use be considered on a case-by-case basis, and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy.” --NIH Consensus Statement on HCV, 2002

The data

As it exists….

HCV Treatment in Methadone Patients

P = NS

36

53

24

40

Overall SVR Relapsed and

Returned toTreatment

Relapsed and Did Not

Return to Treatment

Did NotRelapse

Backmund M, et al. Hepatology. 2001;34:188-193.

0

20

40

60

80

100

Pat

ien

ts (

%)

SVR Rates in Injection Drug Users in Detox (N = 50)

n=10n=15 n=25

Attendance predicts SVR

Backmund M, et al. Hepatology. 2001;34:188-193.

45

6

0

20

40

60

80

100

>2/3 Appts <2/3 Appts

SV

R, %

n=12n=38

P <0.05

Mauss, et al. (Hepatology, 2004)

42

56

0

20

40

60

80

100

MMT Control

SV

R % MMT

Control

p=0.16

n=50n=50

HCV Treatment in the Setting of Active Drug Use

0

48

31

7.6

6150

Noncompliance End of TreatmentResponse

SVR

Pat

ien

ts (

%)

Active IDUs

Nonactive IDUs

P = NS

HCV Treatment Outcomes: Active IDUs vs Nonactive IDUs (N = 406)

Robaeys G, et al. Eur J Gastroenterol Hepatol. 2005;18:159-166.

0

20

40

60

80

100P = NS

P = NS

SVR Rate May Increase with Abstinence

≥ 6 mo< 6 moNoneOccasionalRegular

Abstinence DurationSubstance Use

22

30

35

21

0

Sylvestre DL, et al. J Subst Abuse Treatment. 2005;29:159-165.

10

20

30

40

Su

stai

ned

Vir

olo

gic

Res

po

nse

(%

)

Degree of Drug Use and SVR (N = 76)

0

P = .18P = .09

Protective Immunity?

Patients with ongoing or prior HCV infection may develop immunity that protects against further infection with HCV despite repeated exposure

• Dove L, Phung Y, Bzowej N, Kim M, Monto A, Wright TL. Viral evolution of hepatitis C in injection drug users. J Viral Hepat. 2005 Nov;12(6):574-83.

• Grebely J, Conway B, Raffa JD, Lai C, Krajden M, Tyndall MW. Hepatitis C virus reinfection in injection drug users. Hepatology. 2006 Nov;44(5):1139-45.

• Currie S, Tracy D, Ryan J, Belaye T, Kim M, Monto A. Injection drug users who resolve the HCV virus appear to be protected from reinfection. AASLD 2006: 167A.

Current Studies at OASIS

A Brief HCV Prevention Education Intervention for In- and Out-of-Treatment Drug Users

CDC U50/CCU923257

Protocol• Two test populations, two video

curricula:– Out of treatment drug users at syringe

exchange, n=100• Brief, 7-minute peer-based prevention education

video

– In-treatment drug users enrolled in methadone maintenance, n=450

• 30 minute peer based education video– Two viewing formats: single session vs. 4 session

Protocol• Demographic/risk behavior questionnaire• Randomization:

– Usual care vs. video intervention• SEP 1:1• MMT 1:1:1 (1 usual care: 1 single session: 1 4-part viewing)

• KAM test (Knowledge/Attitudes/Motivations) – Baseline– Immediate post video– Week 4– (Week 8)– Week 12

• Free HCV testing and HAV/HBV vaccinations offered

Sample Knowledge Questions: SEP

• Which of the following can transmit HCV infection? (MC)

• How often is hepatitis C passed on by sex?– Never/rarely/frequently/DK

• Which of the following can you get vaccinated for?

• Most people with hepatitis C don’t need treatment: T/F/DK

• Most people with HCV get yellow jaundice: T/F/DK

• Most people with hepatitis C will die from it: T/F/DK

Preliminary Results

MMT SEP

Enrollment 282/450 100/100

Age (x) 46 43

White (%) 42 42

Black (%) 41 50

Latino (%) 10 7

< High School 33% 26%

Uninsured 30% 41%

10 care in ER 23% 42%

Tested for HIV 97% 98%

Tested for HCV 84% 72%

Told HCV+ 59% 67%

Demographics

MMT SEP

HAV Vax 33% 35%

HBV Vax 33% 34%

Active EtOH 51% 73%

Shared works <1yr 17% 25%

Never condom 58% 46%

Always condom 34% 29%

>3 sex partners <1yr 13% 45%

Prev STD 38% 51%

Tattoo in jail 28% 19%

Demographics

0

5

10

15

20

25

30

35

40

45

Post Video Wk 4 Wk 8 Wk 12

% Im

prov

emen

t

Usual

Video

SEP Knowledge

33 21304140n 29 3023

**

**** **

** P<0.001 for difference from usual care at all time points

0

10

20

30

40

50

60

70

Post Video Wk 4 Wk 12

% Im

prov

emen

t

Usual

Single

4-part

MMT Knowledge Scores

8485 52 68 4773 5343n 36

** P<0.001 for difference from usual care at all time points**

**

**

** ****

p=0.02

MMT Attitudes/Motivation

-0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4

Wk 12

Wk 4

Post Video

Change in Score

4-part

Single

Usual46

43

85

68

52

84

64

55

36

n

p=0.02

p=0.01

p=0.19

*

*

*

*

Transitioning Street-Recruited Heroin Users to HCV Treatment using Buprenorphine

NIDA DA015629-01

Study DesignStreet-recruited

Heroin Users

Hepatitis C Viral Testing

Active: 12-24 weeks buprenorphine

Inactive: Ineligible

HCV Treatment, n=50Buprenorphine Maintenance

Not Interested in HCV Treatment: 12 wk buprenorphine taper

24 week buprenorphine taper

Enrollment

• All screened = 415

• Eligible = 275– Ineligible = 140 (33%)

• Not viremic = 94 (23%)• On methadone = 29 (7%)• No opioid addiction = 17 (4%)

RelevanceAll Screened: n=415

68

53

0

10

20

30

40

50

60

70

80

90

100

Eligible Enrolled Start Bupe

% P

atie

nts

n = 275 n = 188 n = 146

Screened Eligible Enroll Start Study Meds

P Value

n 415 275 188 146Age 46

(20-69)

46

(24-69)

46

(24-64)

46

(24-64)

NS

Male 70.4% 74.9% 73.9% 71.2% NSWhite 34.5% 32.0% 31.9% 33.6% NSBlack 37.3% 40.0% 39.4% 41.8% NSLatino 23.9% 23.6% 23.4% 19.2% NS

The study sample is representative

Screened Eligible Enroll Start Bupe

P Value

Yr. exposed 24 25 25 25ALT 46 53 55 54 <0.001*% Cocaine 47.5 50.6 48.6 50.0 NS% Meth 15.6 14.9 13.5 13.2 NS% Alcohol 58.0 50.3 60.1 55.5 NSGenotype 1 76% 76% 78% 77% NS

*Significant for the difference between screened and eligible cohorts

The study sample is representative

Drug Use Week 0-12

0

1020

30

4050

60

70

8090

100

Op Coc Meth MJ

% U

A +

Baseline

Week 4

Week 8

Week 12

`

Treatment Retention (n=146)

108

9383

76 7266

-10

10

30

50

70

90

110

130

150

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Weeks on Buprenorphine

Num

ber o

f Pat

ient

s

58%45%

Interest in HCV Treatment (n=146)

8155

10

Early Bupe termination

Chose HCV Tx

Chose taper

HCV Treatment Outcomes

• Completed treatment, n=37• Early termination, n=18

– 3 incarcerated– 4 medical– 10 FTS– 1 side effects

Outcomes by Genotype

6859

40

62

48

32

91100

64

0

10

20

30

40

50

60

70

80

90

100

Completed ETR SVR

%

All Pts

Geno 1

Geno non-1

37 1026 21 13 732 1120

Relevance to heroin users who initiate buprenorphine

38

26

16

0

10

20

30

40

50

60

70

80

90

100

Start HCV Tx Complete HCV Tx SVR

Per

cent

Relevance to all eligible heroin users

53

2014

8

0

10

2030

40

50

60

7080

90

100

Initiate Bupe Start HCV Tx Complete HCVTx

SVR

Per

cen

t

OASIS Resources

• Providers:– Hepatitis C University

• www.hcvu.org

• Patients:– HepC411