Slide 1

HCV in the HIV infected Patient

David L. Thomas, MD

Advisory Board – Merck & Co.

Slide 2

HCV Treatment Future is Bright

Slide 3

HCV Treatment Present is Challenging for HIV/HCV Coinfected Patients

Slide 4

2008 Management of HIV/HCV Coinfected Patients

• Whom to treat• How to treat• When to stop

Slide 5

56 year old Caucasian male with HIV and HCV infection

• HIV and HCV diagnoses early 1990s; exposures late 1970s

• No ART: CD4+ lymphocyte 782/mm3, HIV RNA <400c/ml

• HCV genotype 1a; HCV RNA 6.4 log IU/ml• ALT 77; INR 1, TB 1.9; creat 1; plts 219K • Liver biopsy 2001: mild fat; no fibrosis

Slide 6

Which would you do next?

A. Repeat liver biopsy B. Check FibroSure C. Peg IFN and RBV, check HCV RNA 4 and

12 wksD. Compliment him on his DNA and followE. Check CD4+ lymphocyte percent

Slide 7

Which would you do next?

Repeat liver biopsy A. Could be progressionB. Could be an error

Slide 8

Three Year Predictive Value of Liver Biopsy Represents Error and Natural History

• 175 HIV/HCV coinfected persons biopsied twice, median 2.9 yrs

• 41 (24%) had ≥ 2pt increase

• Must repeat test 1

8 2 1

45 20 11 8

20 12 2 3

12 7 5 2

2 2 2

2 1

3 2

1

-3

-2

-1

0

1

2

3

4

5

6

-1 0 1 2 3 4

Ishak Fibrosis Stage at Initial BiopsyC

hang

e in

Isha

k Fi

bros

is S

tage

Sulkowski et al AIDS 2007

Slide 9

Sampling error of liver biopsyFibrosis area: 65%

Fibrosis area: 15%Courtesy of M. Pinzani, Florence

Slide 10

Liver Biopsy Readings Have Limited Validity

Sampling error (metavir 2-4 fibrosis)• 161 > 3cm biopsies ‘reduced’ 1.5cm and

1cm and re-scored1

• % “mild”: 3cm 59%; 1.5 cm 68%; 1cm 80%• Specimen diameter reduced:

• 63% mild increased to 87%• sampling error underestimates

fibrosis

1 Colloredo J Hepatol 2003

Slide 11

Which would you do next?

Check FibroSure Reasonable validity in HIV/HCV coinfected persons, especially considering lack of sensitivity and specificity of biopsy

Slide 13

Which would you do next?

Peg IFN and RBV, check HCV RNA 4 and 12 wks

A. Liver disease staging is inaccurate B. Therapeutic trial provides information on

adverse events and response for this patient

Slide 14

FibroSure=0.9; repeat liver biopsy (>2 cm) shows metavir 3 (of 4) fibrosis; mild macro-vesicular fat, moderate activity. Now what?

A. Peg IFN and RBV B. Wait for new HCV drugs

C. AZT-based ARTD. ABC-based ARTE. TDF-based ART

Peg IFN and RBV after

Slide 15

HAART and Treatment of HCV

• ART should be given if indicated by HIV stage

• Insufficient evidence that PegIFN/RBV response is improved

By ART By higher CD4

• Many recommend it anyway, especially with high HIV RNA or CD4 350-500/mm3

Slide 16

NRTI Choice and RBV

• Don’t use ddI and RBV• Avoid AZT and RBV• ? ABC and RBV

1493 HIV/HCV coinfected getting PegRBV 62% No SVR: associated with GT 1/4; viral load;

low RBV trough; ABC (OR 2.22, 0.91-5.40) 2No difference in SVR in 238 TDF versus 52

ABC2

Effect: Bani Sadr J AIDS 2007; 1Vispo Antivir Ther 2008; Mira et al CROI 2008 ABST 1074; No effect: 2Gonzales-Garcia CROI 2008 ABST 1076

Slide 17

Peg and RBV 1.2 g/d was started without ART. Treatment is well tolerated. HCV RNA drops 6.4 to 4.99 log IU at 30 days. Which is best?

A. Stop, no chance of SVRB. Increase Peg dose C. Continue current therapyD. Start pioglitazoneE. Start ART

Slide 18

Baseline HCV RNA was retested with assay with high upper range=7.5 log IU/ml (vs 6.2). Treatment continued. HCV RNA drops to 3.7 log IU at 12 weeks. Which is best?

A. StopB. Reduce Peg IFN dose, stop RBV C. Continue current therapy

Slide 19

Treatment continued. HCV RNA drops to 3.42 log IU at 24 weeks. ALT 58. Which is best?

A. StopB. Reduce Peg IFN dose, stop RBV C. Continue current therapy for 18 monthsD. Stop, start pioglitazone and ART and

restart ART in 6 months

Slide 20

Forms of Virologic Response

1.00E+00

1.00E+01

1.00E+02

1.00E+03

1.00E+04

1.00E+05

1.00E+06

0 4 8 12 24 48 72

NonRapidEarlyIncomplete

Weeks of HCV Treatment

Log

IU H

CV

RN

A

PEG/RBV ~44%

Slide 21

HCV Therapy Generally Should be Stopped Unless >2 logs at 12 wks and undetectable at 24 wks

• No cure• No control

Slide 22

Rare SVR Without Early Virologic Response in HIV/HCV Coinfected Patients

Study Peg RBV Rx No EVR SVR

ACTG 5071 106 63 0

APRICOT 289 85 2

RIBAVIC 205 68 1

Chung NEJM 2004; Torriani NEJM 2004; Carrat JAMA 2004

Slide 23

No Control of HCV Infection in ACTG 5178 (SLAM C)

PegIFN 2a

RBV 1-1.2g/d

PegIFN 2a

OBSERVECONTINUE

RANDOMIZEEVR

_

+

72 Weeks

Bx1 Bx2 Bx3

Sherman and 5178 team CROI 2008

Slide 24

ACTG 5178 SLAM C EVR Was Common

PegIFN 2a

RBV 1-1.2g/d

PegIFN 2a

OBSERVECONTINUE

RANDOMIZEEVR

_

+

72 Weeks

Bx2 Bx3

329 295

112

44.4%

183

55.6%

Bx1

Sherman and 5178 team CROI 2008

Slide 25

ACTG 5178 SLAM C Maintenance Versus Observation

PegIFN 2a

RBV 1-1.2g/d

PegIFN 2a

OBSERVECONTINUE

RANDOMIZEEVR

_

+

72 Weeks

Bx2 Bx3

329 295

112

44.4%

183

55.6%

Bx1

44

42

Sherman and 5178 team CROI 2008

Slide 26

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Cha

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PEG-IFN

N=24

Observe

N=21

• No benefit of 18 months of maintenance

• DSMB stopped study

• Cirrhosis 18% and 21% of maintenance and observation arms

Sherman and 5178 team CROI 2008

ACTG 5178 No Benefit of Maintenance

Slide 29

Treatment stopped. Creat 1.0; ALT 74 IU; INR 1.0; which is best?A. Refer to Dr. Sulkowski for investigational HCV

drug B. Refer to Dr. Fierer for counseling to prevent

secondary transmissionC. Refer to Dr. Afdhal for management of

cirrhosis and transplant evaluationD. All of the above