Management of Patients Co-infected with HCV and HIV: A

Close Look at the Role for DAAs

Susanna Naggie, MDAssistant Professor of MedicineDivision of Infectious Diseases

Disclosures

• Research: Vertex, Anandys, Synexis, Gilead, Merck, BMS

• Advisory Board: Vertex, Boehringer Ingelheim, Janssen

• Speaker: None

HIV & HCV• 10 million people

worldwide• 30% of US patients

with HIV have HCVHIV40

million

Hepatitis C180 million

Staples CT. Clin Infect Dis 1999

D:A:D Study: Liver-Related Deaths in Persons with HIV

DAD Arch Intern Med;2006;166:1632

14.5%

DAD Study Group, Arch Intern Med 2006Thein et al. AIDS 2008; 22:1979

Treatment Response in DAA Era

Treatment

• Goal of treatment:– Clinical trial definition– Sustained virologic response

– What we tell patients…

Cure!

Who to Treat?

• Prior response?• Risk stratification

– Liver Biopsy– Fibroscan/non-invasive testing

• Adherence• Other baseline factors

– Race/ethnicity– Genotype 1 subtype

HCV Genome: Polyprotein

Moradpour Nature Reviews 2007; 5:453-463

Viral Kinetic Parameters

AASLD HCV Treatment Guidelines

PK Interactions: Telaprevir & ARTART Effects on ART Effects on TVR Recommendations

AUC Cmin AUC Cmin

Efavirenz No change 26% 47% telaprevir dose to 1,125mg q8h

Atazanavir/r - 85% 20% 15% Use standard doses

Darunavir/r 40% 42% 35% 32% Do Not Co-Administer

FPV/r 47% 56% 32% 30% Do Not Co-Administer

Lopinavir/r 34% 43% 54% 52% Do Not Co-Administer

Maraviroc No PK Data, Interaction Possible Do Not Co-Administer

Raltegravir 31% - No significant changes

Use standard doses

Van Heeswijk et al. CROI 2011 Abstract 119and ICAAC 2011 Abstract A1-1738a

Part A: no ART

Follow-upPR48 (control) PR

SVRPbo + PR

T/PR TVR + PR Follow-upSVR

PR

Follow-upPR48 (control) PR

SVRPbo + PR

T/PR TVR + PR Follow-upSVR

PR

Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)

Study 110 Design: Randomized, Double-blind, Placebo-controlled Trial of Telaprevir

240 48 72Weeks 12 36 60

SVR12

SVR12

SVR12

SVR121:1

2:1

Dieterich et al. CROI 2012 Abstract 46Barritt and Fried. Gastro 2012; 142:1314

Stopping/Futility Rules

% o

f Pat

ient

s w

ith U

ndet

ecta

ble

HC

V R

NA

n/N= 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22

Dieterich et al. CROI 2012 Abstract 46

Study 110: SVR-12 Interim Analysis

PK Interactions: Boceprevir & ARTART Effects on ART Effects on BOC Recommendations

AUC Cmin AUC Cmin

Efavirenz 20% - 19% 44% Do Not Co-Administer

ETR, RPV No PK Data, Interaction Possible Do Not Co-Administer

Atazanavir/r 35% 49% No change Do Not Co-AdministerDarunavir/r 44% 59% 29% 35% Do Not Co-Administer

Lopinavir/r 34% 43% 44% 35% Do Not Co-Administer

FPV/r, TPV/r No PK Data, Interaction Possible Do Not Co-Administer

Maraviroc No PK Data, Interaction Possible Do Not Co-Administer

Raltegravir No significant changes Use standard doses

Kasserra et al. 18th CROI 2011 Abstract 118; Hulskotte et al. 19th CROI 2012 Abstract 771LB

14

Randomized, double blind, placebo controlled trial of Boceprevir

• Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV– 2:1 randomization (experimental: control)– Boceprevir dose 800 mg TID

• 4-week lead-in with PEG2b/RBV for all patients– PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID

Weeks 12 24 28 48 72

PEG2b+RBV 4 wk

Placebo + PEG2b + RBV44 wk

Boceprevir + PEG2b + RBV44 wk

Follow-upSVR-24 wk

Follow-upSVR-24 wk

PEG2b+RBV 4 wk

Arm 1

Arm 2

Futility Rules

Stopping/Futility Rules

Sulkowski et al. CROI 2012 Abstract 47Barritt and Fried. Gastro 2012; 142:1314

% o

f Pat

ient

s w

ith U

ndet

ecta

ble

HC

V R

NA

n/N= 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61

Treatment Week

SVR-12 Interim Analysis

Sulkowski et al. CROI 2012 Abstract 47

Adverse Events

Jacobson IM, et al. NEJM, 2011. Poordad F, et al. NEJM, 2011

Adverse Event, %TVR-Containing Arms

Mono-infection(N=727) Co-infection (N=38)

PegIFN/RBV Arms

(n = 383)

Pruritus 45-50 39 9-36

Nausea 40-43 34 23-31

Rash 35-37 34 23-24

Anemia 37-39 18 18-19

Diarrhea 28-32 24 18-22

Adverse Event, %BOC-Containing Arms

Mono-infection (N=734) Co-infection (N=64)

PegIFN/RBV Arms

(N=397)

Anemia 49 41 26-29

Dysgeusia 37-43 28 15-18

Telaprevir (TVR)

Boceprevir (BOC)

Other Considerations…Characteristic Good Response Poor Response

HCV GT 1 subtype 1b 1a

Fibrosis 0-2>3 4

Race European/Asian African-descent

Prior treatment Relapse>Partial Null

IFN responsiveness >1log10 decline <1log10 decline

IL28B CC>CT TT

Phase II/III StudiesDrug Class Tx Inclusion RGT Antiretrovirals

TMC-435

NCT01479868

NS3/4A Naive and experienced

Y RPV, Ralt, MVC,T20, TDF, FTC,3TC, ABC*

BI-201335

NCT01399619

NS3/4A Naive and relapsers

Y DRV/r, ATV/r, Ralt, TDF, FTC, EFV, ABC, 3TC, MVC

BMS-790052

NCT01471574

NS5A Naive Y All except PI + NNRTI combo

*Ouwerkerk-Mahadevain 19th CROI Abstract 49

In a nutshell…• Access to DAA is improving

– Daily dosing/fewer AEs– FDA approval 1.5 years

• IFN-sparing is coming• Assess severity of liver disease• Consider HCV therapy

– Treat those who can’t wait OR– Treat those who will be cured– Clinical Trial