When to Treat HCV in our HIV coinfected

patients2013 Perspective

Brad Hare, MD Annie Luetkemeyer, MD Associate Professor of Medicine, UCSF Assistant Professor of Medicine, UCSF

Disclosures

• Brad has received grant support to UCSF from Vertex Pharmaceuticals, Genentech, and serves in an advisory capacity to Bristol-Myers Squibb

• Annie has received research grant support to UCSF from Bristol-Myers Squibb, Gilead, & Vertex

Goals of this activity

• Changing paradigms in HCV treatment with availability of new HCV drugs: FDA approved and in clinical trials

• What to do NOW for HCV-coinfected patients?

• Who should be treated, who can wait?

Glossary

• DAA: Direct Acting Agent. Anti-HCV medications that target specific aspects of HCV viral replication

• PEG: Pegylated interferon• RBV: Ribavirin• PR: PEG + ribavirin• Genotype: Strains of HCV that affect

treatment response (1-6) – Genotypes 1&4 harder to cure than 2&3

• IL28b – human gene that contributes to response to IFN-based treatment– Response from best to worst:

CC>CT>TT

Glossary (2)

•SVR: Sustained virologic response (HCV viral load undetectable off of treatment) SVR12 and SVR24 considered cures

•Null response: Failure to attain at least 2 log10 drop in HCV after 12 weeks of treatment•Response Guided Therapy: Shortening therapy based on good early virologic response (1st 12 weeks)

Case #1

• 35 year old African American man, CD4+ 450, HIV RNA <40 copies/ml, on Atripla

• HCV treatment naïve, HCV RNA 500,000 IU/ml• Genotype 1a, IL28b genotype T/T (least

favorable) • Biopsy: Fibrosis Stage 2 (scale 0-4),

Inflammation Grade 1 (scale 0-4) • No other comorbidities, including psychiatric• In terms of HCV treatment readiness: “I’ll do

whatever you say, Doc”

Case #1 Audience vote, pre-debate

1) Treat now?2) Wait to treat?

Case: 35 y.o. man, HCV Treatment Naïve, Genotype 1a, IL28B genotype T/T (least favorable), Fibrosis Stage 2. HIV well controlled on Atripla

Argument to Treat Now

Telaprevir Boceprevir in coinfection in coinfection

0

10

20

30

40

50

60

70

80

SVR12

TVR

PEG/RBV

Dieterich D, et al. CROI 2012, Abstract 46. Sulkowski M, et al CROI 2012. Abstract 47

74%

45%

0

10

20

30

40

50

60

70

80

SVR12

BOC

PEG/RBV

60.5%

26.5%

Telaprevir works with Atripla(Remember to dose adjust)

Dieterich D, et al. CROI 2012, Abstract 46.

Telaprevir and IL28b

In ADVANCE Study (HIV-negative), TPV improved response across all IL28b genotypes, including T/T

Jacobson I, et al. EASL 2011. Abstract 1369.

SVR Rates in Patients Genotyped for IL28B

SV

R (

%)

T12PR T8PR PR

60

100

80

40

20

0n/N = 45/50 38/45 35/55

CC

48/68 43/76 20/80

CT

16/22 19/32 6/26

TT

90 84

6471

57

25

7359

23

SVR Rates in Patients With RVR

n/N = 39/42 30/32 9/9

CC

36/41 34/47 2/2

CT

10/13 14/16 0/0

TT

93 94100

8872

100

7788

0.00

0.25

0.50

0.75

1.00

0 5 10Time Since Biopsy (years)

Even Fibrosis F2 is Bad

Sulkowski MS et al. CROI 2010. Abstract 166.

11

N = 638 adults

F0 F1 F2 F3 F4

Risk of End-Stage Liver Disease, Hepatocellular Carcinoma and Liver Related Death by Fibrosis Score in Co-Infected Patients

Fra

ctio

n no

t mee

ting

an e

ndpo

int

Argument to Wait

74%

45%

N=76 N=44

48 weeks of PEG/RBV + Telaprevir12 weeks of 3-4 oral drugs

Dieterich D, et al. CROI 2012, Abstract 46. Kowdley AASLD 2012

Argument to Wait

• IL28b T/T: up to 25% worse SVR compared to C/C1 (HIV negative)

• African American response with HCV PI’s < White patients (SVR AA 50-62% vs. non-AA 68-75%2)

• No data yet to support response guided therapy in HIV+– Therefore 48 weeks of therapy

• Relatively young patient with intermediate fibrosis - can afford to wait and will spare himself a year of toxicity by doing so

1 Kwo Liver Int 2011; 32(S1):39 2 Burton SMJ 2012;105(8):431

Rebuttal: Treat Now

Rebuttal: Wait to treat

Case #1 Audience vote, post-debate

1) Treat now?2) Wait to treat?

Case: 35 y.o. man, HCV Treatment Naïve, Genotype 1a, IL28B genotype T/T (least favorable), Fibrosis Stage 2. HIV well controlled on Atripla

Case #2• 60 year old Caucasian man, CD4+ 815, HIV RNA

< 40 copies/ml on Raltegravir/Epzicom• Treatment naïve, HCV Genotype 3a, HCV RNA

1.2 million IU/ml, HCV infection “since the 70’s”• Normal platelets and coagulation• Ultrasound: no evidence of cirrhosis• Mild depression, well controlled on SSRI, no

other comorbidities. • “I’ll do whatever you recommend, except stick

a needle in my liver!”

Case #2, Audience vote, pre-debate

1) Treat now?2) Wait to treat?

Case: 60 y.o. man, HCV treatment naïve, Genotype 3a, no cirrhosis by imaging, HIV well controlled on raltegravir+ Epzicom

Study Cohort RxSustained Virologic

Response Rate

RIBAVIC1

2004

Peg IFN α-2bRBV 800mg QD

OverallGenotype 1Genotype non-1

27%15%43%

ACTG 50712

2004

Peg IFN α-2aRBV 600mg → 800mg QD

OverallGenotype 1Genotype non-1

27%14%73%

APRICOT3

2004

Peg IFN α-2aRBV 800mg QD

OverallGenotype 1Genotype non-1

40%29%62%

PRESCO4

2007

Peg INF α-2aRBV 1000mg (<75kg) or RBV 1200mg (>75kg) QD

OverallGenotype 1Genotype non-1

50%35%72%

1 Carrat F JAMA 20042 Chung R NEJM 20043 Torriani FJ NEJM 2004

4 Nunez M AIDS Research and Human Retroviruses 20075 Rodriguez-Torres AASLD 2009 #1561

Argument to Treat now

Argument to Treat now Treating at a younger age associated with better cure rates

Mauss CROI 2012 #763

Our patient is 60 years old

Kirk GD HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort StudyAnn Intern Med. 2013

Liver fibrosis and age among persons coinfected with HIV and HCV and those with only HCV.

For each age, predicted liver fibrosis scores were calculated using a regression equation that included the race, sex, alcohol use, body mass index, hepatitis B virus surface antigen level status, and HCV RNA level values for a representative participant (black overweight male who has no regular alcohol use, is hepatitis B virus surface antigen–negative, and has high HCV viral load) for persons coinfected with HIV and HCV (dashed line) and for persons with only HCV (solid line). For example, a 40-year-old HIV and HCV coinfected person with these characteristics was calculated to have a predicted FibroScan score of 9.04 kPa. For this same degree of fibrosis, the predicted age in a similar person but with only HCV was 49.2 years. Over the entire age range, the average difference in estimated age between persons coinfected with HIV and HCV and those with only HCV was 9.2 years (90% coverage limit, 5.2 to 14.3 years). HCV = hepatitis C virus.

More Fibrosis in HIV+

Argument to Wait

Fatigue 36% 36% 40%

Pyrexia 32% 35% 41%

Headache 34% 29% 35%

Myalgia 27% 29% 32%

Nausea 19% 19% 22%

Insomnia 23% 16% 19%

Asthenia 23% 20% 26%

Depression 20% 16% 20%

IFN PEG PEG+ RBV + placebo + RBV

(n = 285) (n = 286) (n = 288)

Torriani et al. 11th CROI, 2004; Abstract 112

Treatment related side effects in Apricot study of HIV/HCV coinfection

What’s coming for Geno 2/3

Sofosbuvir (nuc) + RBV x 12 wks + pegIFN x 4-12 wks

Sofosbuvir (nuc) + RBV x 12 wks

Sofosbuvir (nuc) + daclatasvir (NS5A) ± RBV x 24 wks

100

80

60

40

20

0

SV

R12

or

24 (

%)

100[1] 100[1]

Geno 2/3 Naive

96[2]

1. Gane EJ, et al. AASLD 2012. Abstract 229. 2. Sulkowski M, et al. AASLD 2012. Abstract LB-2.

Rebuttal: Treat Now

Rebuttal: Wait to treat

Case #2, Audience vote, post-debate

1) Treat now?2) Wait to treat?

Case: 60 y.o. man, HCV treatment naïve, Genotype 3a, no cirrhosis by imaging, HIV well controlled on raltegravir+ Epzicom

Case #3• 48 y.o. Latina woman, CD4+ 388, HIV RNA < 40

copies/ml on Atazanavir/ritonavir + Truvada• Genotype 1b, HCV RNA 750,000 IU/ml, IL28b

genotype C/T (intermediate) • PEG/RBV 4 years ago, stopped after 12 weeks

due to < 2 log10 HCV RNA drop (null response), tolerated reasonably well

• Imaging now suggestive of early cirrhosis, biopsy Fibrosis stage 3-4, no history of decompensation

• No other signficant comorbidities

Case #3, Audience vote, pre-debate

1) Treat now?2) Wait to treat?

Case: 48 y.o. woman, prior null responder, HCV Genotype 1b, Fibrosis stage 3-4, IL28b C/T (intermediate). HIV well controlled on Atazanavir/ritonavir + Truvada

Argument to Treat NowShe has early cirrhosis – don’t wait

Survival among HIV/HCV Coinfected patients with cirrhosis

Lopez-Dieguez, M; AIDS. 25(7):899-904, April 24, 2011.

Telaprevir is the best option

Butt A, and Kanwal F Clin Infect Dis. 2012;54:96-104

REALIZE study of retreatment in individuals with prior treatment failuresHIV negative

Argument to Wait

Bourliere Liver International 2012 Feb;32 Suppl 1:113-9

Cross-resistance of NS3 Protease Inhibitors

V36A/MR155K/T/Q/P

V55AA156/V/T

V170A/T/L

D168A/V/T/H

T54S/A

*Mutations associated with in vitro resistance but not described in patients.

Susser S et al. Hepatology. 2009;50:1709-18; Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.

A156SQ80R/K

* *

*

* * Telaprevir

Narlaprevir

Danoprevir

TMC 435

BI 201335

MK-7009

BoceprevirLine

arM

acro

cycl

ic

DAA regimens in Nulls & Cirrhosis

90% SVR rate

GT1a GT1b

43

0

20

40

60

80

3/ 7

57

8/ 14

TID16, 28, 40

+

BID28+

TID28-

50

2/ 4

80

4/ 5

11 2/ 18

60

15/25

Cirrhosis No Cirrhosis

TID16, 28, 40

+

BID28+

TID28-

0/ 0

33

1/ 3

42

11/26

86

37/43

43

40/93

68

84/124

n/ N =

12 weeks of HCV PI + NS5A in Null Responders, Genotype 1b (BMS)

SOUND-C (HCV Protease inhibitor + polymerase+ RBV) cirrhosis subanalysis

80% SVR rate

Zeuzem S, et al. AASLD 2012. Abstract 232. Chayama Hepatology 2012 Mar;55(3):742-8

Rebuttal: Treat Now

Rebuttal: Wait to treat

Case #3, Audience vote, post-debate

1) Treat now?2) Wait to treat?

Case: 48 y.o. woman, prior null responder, HCV Geno 1b, Fibrosis stage 3-4, IL28b C/T (intermediate). HIV well controlled on Atazanavir/ritonavir + Truvada

Summary

• HCV treatment is in a very dynamic period with the promise of improved SVR rates, shorter treatment and improved tolerability– Certain patients are likely to remain more challenging

to treat: HIV coinfection, cirrhotics, prior non-responders

• Less data are available for HIV co-infected patients and there may be more wrinkles– Drug-drug interactions– Possibly lower SVR rates than mono-infection

• Patients and clinicians are left to apply limited data and weigh available options against hopeful, but uncertain, future options