P-1

Douglas T. DIETRICHDouglas T. DIETRICH

P-2

Treatment of HCV in HIV Disease: Treatment of HCV in HIV Disease: New Challenges, New PromiseNew Challenges, New Promise

Douglas T. Dieterich, M.DDouglas T. Dieterich, M.DProfessor of MedicineProfessor of Medicine

Division of Liver Diseases,Division of Liver Diseases,

Gastroenterology and Infectious DiseasesGastroenterology and Infectious Diseases

Director of CMEDirector of CME

Department of MedicineDepartment of Medicine

Mt. Sinai School of MedicineMt. Sinai School of MedicineNew York, New YorkNew York, New York

P-3

Hospital Admissions for Liver Complications Hospital Admissions for Liver Complications Increased 5-Fold (1995–2000)Increased 5-Fold (1995–2000)

Gebo KA, et al. JAIDS. 2003;34:165-173.

0

10

20

30

40

Ho

spit

aliz

atio

ns

per

Ho

spit

aliz

atio

ns

per

Pat

ien

t-Y

ears

Fo

llo

w-U

pP

atie

nt-

Yea

rs F

oll

ow

-Up

1995 1996 1997 1998 1999 20001995 1996 1997 1998 1999 2000

Opportunistic infectionsOpportunistic infections

IDU-related complicationsIDU-related complications

Liver-related complicationsLiver-related complications

P-4

Liver disease is a major cause Liver disease is a major cause of death in the ART eraof death in the ART era

Bica et al. Clin Infect Dis 2001; 32:492–497Puoti et al. JAIDS 2000; 24:211–217Soriano et al. Eur J Epidemiol 1999; 15:1–4Soriano et al. PRN Notebook 2002; 7:10–15Martin-Carbonero et al. AIDS Res Human Retrovirus 2001; 17:1467–1471

0

10

20

30

40

50

60

Mo

rtal

ity

(%)

Death from end-stage liver disease (ESLD) as a% of all deaths among HIV patients

Italy (Brescia) Spain (Madrid) USA (Boston)

13%

35%

5%

12%

45%

50%Pre-HAART era

HAART era

P-5

Causes of Liver Disease in HIV InfectionCauses of Liver Disease in HIV Infection

P-6

Ishak fibrosis stage on second biopsy among Ishak fibrosis stage on second biopsy among persons with little or no fibrosis on first biopsy persons with little or no fibrosis on first biopsy

Sulkowski MS et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-172). Boston, MA USA, February 22–25, 2005

Median (IQR) time between bxs, 2.84 yrs (2.05–3.41)

28% with more than 2 stage progression

n = 51

45%

23%

10%14%

8%

0

20

40

60

0 1 2 3 or 4 5 or 6Fibrosis stage at second biopsy

Pat

ien

ts (

%)

P-7

FibroScanFibroScan

2.5 cm

4 cm

1 cm

Explored volume

LB: 1/50,000 of the liver

FibroScan: 1/500 of the liver

The probe induces an elastic wave through

the liver

The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface

P-8

Transient Elastography in HIV HCV Transient Elastography in HIV HCV Co-infected PatientsCo-infected Patients

72 patients with simultaneous liver biopsy 72 patients with simultaneous liver biopsy and Fibroscanand Fibroscan

Liver stiffness 3.0 to 46.4 kilopascalLiver stiffness 3.0 to 46.4 kilopascalLiver stiffness correlated signficantly to Liver stiffness correlated signficantly to

fibrosis stage p < 0.0001fibrosis stage p < 0.0001AUROC(area under receiver operating curve) AUROC(area under receiver operating curve)

was .72 for F>2 and .97 for F=4. was .72 for F>2 and .97 for F=4. F=4 was > plt count, AST/ALT ratio, APRI, F=4 was > plt count, AST/ALT ratio, APRI,

and FIB 4and FIB 4

De Ledinghen et al J Acquir Immune Defic Syndr 41: 175-179

P-9

Liver BiopsyLiver Biopsy

Gold standard for grading and staging diseaseGold standard for grading and staging disease Invasive, expensiveInvasive, expensiveNeedle liver biopsy samples < 1/50,000th of the Needle liver biopsy samples < 1/50,000th of the

liverliver Incorrect staging of 1 stage in 10% to 20% of Incorrect staging of 1 stage in 10% to 20% of

casescases Dependent onDependent on

• Length of biopsyLength of biopsy——25 mm optimal (16%)25 mm optimal (16%)• Number of biopsies performed Number of biopsies performed • Type of biopsy needle usedType of biopsy needle used• Etiology of liver diseaseEtiology of liver disease

P-10

The Importance of Liver BiopsyThe Importance of Liver Biopsy

P-11

Conflicting Data on the Effects of HCV Conflicting Data on the Effects of HCV Upon HIV DiseaseUpon HIV Disease

Meta-analysis involving 6216 patients from 8 trials Meta-analysis involving 6216 patients from 8 trials Mean increase in CD4 cell count among HIV/HCV Mean increase in CD4 cell count among HIV/HCV

coinfected patients was 33.4 cells/mmcoinfected patients was 33.4 cells/mm33 less than that less than that observed in HIV-monoinfected patientsobserved in HIV-monoinfected patients

EuroSIDAEuroSIDA After adjusting for baseline factors, investigators After adjusting for baseline factors, investigators

concluded that HIV/HCV-coinfected patients do not concluded that HIV/HCV-coinfected patients do not have a greater risk of progressing to AIDShave a greater risk of progressing to AIDS

Miller et al. Clin Inf Dis. 2005;41:713-720. Rockstroh et al. J Inf Dis. 2005;192:992-1002

P-12

Significant increase in new acute HCV Significant increase in new acute HCV infections in 2003infections in 2003

• Test for trend p-value using Poisson regression p<0.001• Error bars = 95% CI

Inci

den

ce o

f ac

ute

HC

V i

nfe

ctio

n/1

000

pt

yrs

0

5

10

15

20

25

30

1997 1998 1999 2000 2001 2002 2003

Browne RE, et al. 2nd IAS 2003; Abstract 972

P-13

HCV: A new epidemic among MSM?HCV: A new epidemic among MSM?

Newly infected male, MSM, HCV+ patients at a Newly infected male, MSM, HCV+ patients at a London clinic, January 1997 – May 2003; London clinic, January 1997 – May 2003; n=44n=44

Reasons for testing: Reasons for testing: ALT (35), sexual ALT (35), sexual contact with HCV+ person (3), jaundice (3), contact with HCV+ person (3), jaundice (3), HIV screening (2), H/O IVDU (1)HIV screening (2), H/O IVDU (1)

Risk factors identified: IVDU (1), sexual Risk factors identified: IVDU (1), sexual contact (39), none (4)contact (39), none (4)

Browne RE, et al. 2nd IAS 2003; Abstract 972

P-14

HIV-positive MSM with acute HCV HIV-positive MSM with acute HCV infection in 3 hospital wards in Paris, infection in 3 hospital wards in Paris,

France (n=29)France (n=29)N

um

ber

of

pat

ien

ts

4

3

2

1

0Jan Apr Jul Oct Jan Apr Jul Oct Jan Apr Jul Oct Jan Apr Jul Oct

2001 2002 2003 2004Year

Gambotti L. Eurosurveillance 2005; 10: 115

P-15

Possible transmission risk factorsPossible transmission risk factorsResults of anonymous questionnaire (n=11)Results of anonymous questionnaire (n=11)

Unprotected anal sex with casual partner within six months prior to hepatitis

(n=11)

Met sex partner at gay venue or via internet

(n=11)

STI reported (n=10):-syphilis (n=6)-gonorrhoea (n=3)-genital herpes (n=3)-chlamydia (n=3)-warts (n=3)-anal/genital infection (n=3)

‘Hard sex’ (n=8):-fisting (n=5) -bleeding (n=6)

Inhaled poppers during sex (n=11)

Used psychoactive drugs during sex (n=5)

Tattoos or piercing within 6 months prior to hepatitis C (n=3)

Gambotti L. Eurosurveillance 2005; 10: 115

P-16

German acute Hepatitis C Trial – I (1998–2000) German acute Hepatitis C Trial – I (1998–2000) interferon alfa-2b monotherapy for 6 monthsinterferon alfa-2b monotherapy for 6 months

98%

0%

20%

40%

60%

80%

100%

0 4 8 12 16 20 24Weeks

HC

V R

NA

neg

ativ

e

48(F/up Wk 24)

n=44

Jaeckel E, et al. N Engl J Med 2001; 345: 1452

P-17

Acute HCV in IVDU: Swiss Association for the Acute HCV in IVDU: Swiss Association for the Study of the Liver Study (SASL 18)Study of the Liver Study (SASL 18)

27 patients 5 spontaneous clearance

22 patients treatment indicated

6 refused therapy2 patients lost to observation

14 patients Peg-IFN treatment started

6 premature stop due to side-effects (1 SVR)

8 patients adherent to

therapy7 patients with SVR

Broers, B et al. J Hepatol 2005; 42: 323

P-18

Hep-Net Acute HCV Study HCV-IIHep-Net Acute HCV Study HCV-II

0

20

40

60

80

100

Pa

tie

nts

(%

)

ETR SVR

71%

82%

ITT; n=89ETR SVR

94%89%

Pts. adherent to therapy; n=65Adherent to therapy = 80% of pegylated interferon dose, 80% of treatment durationWiegand et al. (Submitted)

P-19

Response to treatment :Response to treatment :acute HCV infection in HIV+ patientsacute HCV infection in HIV+ patients

0

20

40

60

80

100

All Patients(n=27)

Genotype 1(n=20)

Genotype non-1(n=4)

67% 65%

100%

59% 55%

SVRETR

Vir

olo

gic

al r

esp

on

se (

%)

Pegylated interferon alfa-2b (1.5 g/kg/wk) + ribavirin (800–1200 mg/day) for 24 weeks

100%

Nelson M, et al. 3rd IAS 2005; Abstract TuPe1.1C10

P-20

Hôpital Pitié-Salpêtrière, Hôpital Pitié-Salpêtrière, Paris, France (n=14)Paris, France (n=14)

Week 12 Week 24 Week 48 (SVR)

HC

V R

NA

<50

IU

/mL

(%

pat

ien

ts)

Peg-IFN alfa-2a (40KD) 180 μg/wk plus ribavirin 800 mg/day for 24 weeks

86%79%

71%

0

10

20

30

40

50

60

70

80

90

100

Dominguez S, et al. 10th EACS 2005; Oral presentation PS7/6

P-21

Acute HCV at Mount Sinai Liver Biopsy Series of Acute HCV at Mount Sinai Liver Biopsy Series of 7: Risk Factors7: Risk Factors

11 22 33

Unprotected receptive Unprotected receptive anal intercourseanal intercourse

YesYes

Hundreds of Hundreds of partnerspartners

YesYes

Multiple Multiple partnerspartners

YesYes

About 50 About 50 partnerspartners

Recent STDsRecent STDs NoneNone NoneNone NoneNone

IVDUIVDU NoNo RecentRecent RecentRecent

Shared snorting Shared snorting paraphernalia paraphernalia

YesYes NoNo NoNo

Methamphetamine Methamphetamine IntoxicationIntoxication

YesYes YesYes YesYes

P-22

The Biopsy of Case 1 Had The Biopsy of Case 1 Had FibrosisFibrosis Typical of Damage Caused by Typical of Damage Caused by ChronicChronic HCV HCV

Mild portal inflammation, interface hepatitis, and lobular necroinflammatory activity. Portal fibrosis with occasional fibrous septum formation on trichrome stain (panel C). Immunostains for HBsAg and HBcAg were negative (not shown). Arrows in panel B identify a region of focal interface hepatitis; arrows in panel C indicate fibrous septae (blue).

P-23

Case 2 Also Had Evidence of Chronic InjuryCase 2 Also Had Evidence of Chronic Injury

Marked expansion of portal tracts by fibrosis and inflammation. Lymphoid aggregates. Moderate interface hepatitis and lobular necroinflammatory activity. Mild steatosis. Trichrome stain reveals portal and periportal fibrosis with rare fibrous septum formation. HBsAg and HBcAg were not detectable by IHC (not shown). Arrow in B marks an expanded portal tract with a lymphoid aggregate; arrows in C indicate portal and periportal fibrosis.

P-24

Fat In The Wrong Places Fat In The Wrong Places And Insulin ResistanceAnd Insulin Resistance

% Intramuscularfat in HIV+ men

(Sakkas, unpubl, 2003)

HOMA-IR

Liver (Sutinen AIDS 2002): Significantly higher % liver

fat in HIV+ LD vs. HIV+ no LD and HIV-

Severity of insulin resistance related to liver fat but not VAT

R2 = 0.7938P < 0.01

0

2

4

6

8

0 2 4 6 8 10

P-25

NAFLD: the hepatic manifestation NAFLD: the hepatic manifestation of the metabolic syndromeof the metabolic syndrome

Obesity

Diabetes

Hypertension

Hyper-

triglyceridemia NAFLD

47 million have metabolic syndrome~80% have NAFLD15% of US population has a fatty liver3-4% have NASH

P-26

NASH is associated with mitochondrial NASH is associated with mitochondrial paracrystalline inclusionsparacrystalline inclusions

NASH Fatty liver

Sanyal et al, Gastro, 2001, 120:1183-1192

P-27

NASH: pre vs post treatment with NASH: pre vs post treatment with pioglitazone + vitamin Epioglitazone + vitamin E

Pre treatment (10 X) Post treatment (10 X)

Sanyal et al, Clin Gastroenterol and Hepatol, Dec 2004

P-28

Insulin Resistance and HCV:Insulin Resistance and HCV:Effect on Response toEffect on Response to PegIFN/RBV Therapy PegIFN/RBV Therapy

60.5

40

20

0.0

20.0

40.0

60.0

80.0

100.0

HOMA <2 HOMA 2-4 HOMA >4

% S

VR

in

Gen

oty

pe

1

Homa: Homeostasis model of assessment – HOMA of insulin resistanceRomero-Gomez, M et al. Gastroenterology 2005;128:636-641.

P-29

Does steatosis Does steatosis affect response to treatment? affect response to treatment?

Geno 2F0-1

Per

cen

t S

VR

98%

59%

F2,3,4

59%

High Viral Load

57% 51%39%

Geno 1,4.5.6

Geno 1,4.5.6

High V Load

Geno 1,4.5.6

High V LoadF2,3,4

89%

41% 40%35% 24%

21%

Poynard et al. Hepatology 2003.

No steatosis

Steatosis

P-30

Insulin resistance and NAFLD Insulin resistance and NAFLD in co-infectionin co-infection

Results:Results:In univariate analyses global and semi-quantitative measures of In univariate analyses global and semi-quantitative measures of steatosis strongly associated with HOMA-IR (p<0.0001) -see steatosis strongly associated with HOMA-IR (p<0.0001) -see plotplot

ALT (p=0.003) AST (p=0.003)ALT (p=0.003) AST (p=0.003)genotype (p=0.049) negative once genotype 3 excludedgenotype (p=0.049) negative once genotype 3 excludedethnicity (p=0.024)ethnicity (p=0.024)

Significant correlation between HOMA-IR and HAI fibrosis stage Significant correlation between HOMA-IR and HAI fibrosis stage (p=0.011) and steatohepatitis stage (p=0.005)(p=0.011) and steatohepatitis stage (p=0.005)BMI correlated with HOMA-IR (p=0.0085) but not histological BMI correlated with HOMA-IR (p=0.0085) but not histological parametersparameters

In logistic regression analyses onlyIn logistic regression analyses only IR positively associated IR positively associated (p=0.015 OR=1.08 95%CI 1.01-1.14) with moderate/severe (p=0.015 OR=1.08 95%CI 1.01-1.14) with moderate/severe steatosissteatosis

P-31

Insulin resistance and NAFLD inInsulin resistance and NAFLD in co-infection co-infection

0

10

20

30

40

50

60

No Yes

EVR

r = -0.282 p = 0.031

Baseline Insulin Resistance by EVR

P-32

RIBAVIC- ANRS HC02RIBAVIC- ANRS HC02mitochondrial toxicity event » (MTE)mitochondrial toxicity event » (MTE)

6 acute pancreatitis (one with hyperlactatemia)6 acute pancreatitis (one with hyperlactatemia) 7 hyperlactatemia (hospitalization)7 hyperlactatemia (hospitalization) 4 suspicions of hyperlactatemia 4 suspicions of hyperlactatemia Association with Didanosine treatment*Association with Didanosine treatment*

Odds-ratio for ddi = 23 [95% CI : 5-105]

ddI d4T % with MTE

yes yes

yes no

no yes

no no

24% (12/50)

7% (3/30)

0% (0/114)

2% (2/98)

P-33

Occurrence of Hepatic DecompensationOccurrence of Hepatic DecompensationAPRICOTAPRICOT

1.6%

10.5%

0%0

2

4

6

8

10

12

All Patients Cirrhotic Patients(non-decompensated)

(n = 133)

Non-cirrhotic Patients (n = 735)

Pat

ien

ts (

%)

(N = 868)

n = 14 n = 14

P-34

Risk FactorsRisk Factors

Total bilirubin Total bilirubin (OR 1.12, P<0.001) (OR 1.12, P<0.001)Alkaline phosphatase Alkaline phosphatase (OR 1.02, P<0.001) (OR 1.02, P<0.001)Albumin Albumin (OR 0.83, P<0.002) (OR 0.83, P<0.002)Platelets Platelets (OR 0.96, P<0.001) (OR 0.96, P<0.001)Hemoglobin Hemoglobin (OR 0.53, P=0.001) (OR 0.53, P=0.001)Didanosine treatment (OR 4.06, P=0.03)Didanosine treatment (OR 4.06, P=0.03)Lamivudine treatment (OR 0.30, P=0.04)Lamivudine treatment (OR 0.30, P=0.04)PT INR, efavirenz, saquinavir and non-PT INR, efavirenz, saquinavir and non-

nucleoside inhibitor treatments (P<0.20)nucleoside inhibitor treatments (P<0.20)

P-35

Ribavirin and Ribavirin and ddIddI = “ = “ddon’t on’t ddo o iit”t”

ddI

ddI-MP

ddA-MP

ddA-DP

ddA-TP

RT -Pol

(-) (-)

Inositol IMP XMP GTPIMP dehydrogenase

Ribavirin-MP

Ribavirin

(-)

Adenosine kinase

Ribavirin increases IMPRibavirin increases IMP• Increases ddATPIncreases ddATP• Increases inhibition of HIV RTIncreases inhibition of HIV RT• Increases inhibition of host g-polIncreases inhibition of host g-pol

P-36

Summary of Results Summary of Results From Coinfection Trials From Coinfection Trials

Study N Treatment SVR (%)

All GT 1 GT non-1

RIBAVIC 412 PEG IFN α-2b + RBV 800 27 17* 44 IFN α-2b + RBV 800 20 6 43

ACTG 133 PEG IFN α 2a + RBV 600 27 14 73 IFN α -2a + RBV 600 12 6 33

APRICOT 860 PEG IFN α 2a + RBV 800 40 29 62IFN α -2a + RBV 800 12 7 20

LAGUNO 93 PEG IFN α-2b + W/B RBV 44 38 53IFN α-2b + W/B RBV 21 7 47

PRESCO 389 PEG IFN α-2a + W/B RBV 5050 36 72 36 72G1 48 w 31 72w 52G1 48 w 31 72w 52G2 24 w 67 48w 82G2 24 w 67 48w 82

P-37

12%12%

n = 285

20%20%

n = 286

40%40%

n = 289

Apricot Apricot Sustained Virologic Response*Sustained Virologic Response*

PP = 0.0084 = 0.0084

PP 0.00010.0001

PP 0.00010.0001

* Defined as <50 IU/mL HCV RNA at week 72; ITT* Defined as <50 IU/mL HCV RNA at week 72; ITT

% R

esp

on

se%

Res

po

nse

0%0%

10%10%

20%20%

30%30%

40%40%

50%50%

60%60%

IFN alfa-2a + RBVIFN alfa-2a + RBV PEG-IFN alfa-2aPEG-IFN alfa-2a(40 kDa) + (40 kDa) + PlaceboPlacebo

PEG-IFN alfa-2aPEG-IFN alfa-2a(40 kDa) + RBV(40 kDa) + RBV

P-38

Results: treatment factors Results: treatment factors predictive of an SVRpredictive of an SVR

The relationship between The relationship between various treatment factors and various treatment factors and SVR rates were examinedSVR rates were examined

Cumulative peginterferon-Cumulative peginterferon-alfa-2a (40KD) dose was alfa-2a (40KD) dose was strongly correlated with strongly correlated with cumulative ribavirin dose cumulative ribavirin dose (r=0.87)(r=0.87)

Ribavirin dose also correlated Ribavirin dose also correlated with ribavirin treatment with ribavirin treatment duration (r=0.98) duration (r=0.98)

0

20

40

60

100

80

0 20 40 60 80 100

Cumulative ribavirin dose

Cu

mu

lati

ve p

egin

terf

ero

n-

alfa

-2a

(40K

D)

do

se

SVR No SVR

P-39

MLR analysis: impact on SVR ratesMLR analysis: impact on SVR rates

Receipt of ≥80/80/80(vs <80/80/80)

Body mass index(per 1 unit increase)

Baseline HCV RNA(per 1-log increase)

0.1 1.0 10.0

0.85 (0.75–0.95) (p=0.0062)

0.32 (0.19–0.54) (p<0.0001)

6.55 (2.43–17.7) (p=0.0002)

Odds ratio (95% CI)

Less likely to have an SVR More likely to have an SVR

Only factors with a significant (p<0.05) effect are shown

P-40

74%

22%

4%

62%

30%

8%

69%

26%

5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Histological Response in Patients Histological Response in Patients with an SVRwith an SVR

% o

f P

atie

nts

% o

f P

atie

nts

No Change = Change of +1, -1 or 0 in HAI score;No Change = Change of +1, -1 or 0 in HAI score;Worsening = Worsening = ≥2-point increase in HAI score≥2-point increase in HAI score

n = 19 n = 1 n = 3 n = 4n = 11n = 6n = 51n = 23n = 20

ImprovedImproved No changeNo change WorsenedWorsened

PEG-IFN alfa-2a (40KD) + Placebo

IFN alfa-2a + RBV

PEG-IFN alfa-2a (40KD) + Placebo

PEG-IFN alfa-2a (40KD) + RBV

P-41

32%

43%

25%30%

36% 34%

43%

34%

23%

Histological Response in Patients Histological Response in Patients without an SVRwithout an SVR

n = 21 n = 26 n = 33 n = 14n = 35n = 45n = 26n = 29n = 340%

10%

20%

30%

40%

50%

60%

70%

80%

% o

f P

atie

nts

% o

f P

atie

nts

ImprovedImproved No changeNo change WorsenedWorsened

IFN alfa-2a + RBV

PEG-IFN alfa-2a (40KD) + Placebo

PEG-IFN alfa-2a (40KD) + RBV

No Change = Change of +1, -1 or 0 in HAI score;No Change = Change of +1, -1 or 0 in HAI score;Worsening = Worsening = ≥2-point increase in HAI score≥2-point increase in HAI score

P-42

Zidovudine: impact on HCV treatmentZidovudine: impact on HCV treatment

HB decrease by week 4

3.14

1.96

0

1

2

3

ZDV No ZDV

HB

lo

ss (

g/d

l)

RBV dose reduction by week 4

52%

20%

0%

20%

40%

60%

ZDV No ZDVP

atie

nts

wit

h R

BV

dec

reas

e

Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

P-43Dieterich D, et al. CROI 2004

Hematologic ResponseHematologic Response

101Baseline

Epoetin alfa (n=30)SOC (n=22)

2 3 4 8 12 16

11

12

13

14

Hematologic Response

Time (Weeks)*P<.001 vs. BL†P<.001 for epoetin alfa vs. SOC.‡P=.503 vs. BL

*

 

‡

13.7 ± 0.4

11.7 ± 0.3

†

P-44

Hematologic Response: AZT vs. no AZTHematologic Response: AZT vs. no AZT

Dieterich D, et al. CROI 2004

101Baseline 2 3 4 8 12 16

11

12

13

14

Hematologic Response: AZT vs. no AZT

T ime (W eeks)

‡

 13.8 ± 0.513.6 ± 0.7

12.3 ± 0.5

11.0 ± 0.4

*

*P<.090 for epoelin alfa-treated patients receiving AZT vs. not receiving AZT.†P<.001 for epoetin alfa-treated patients receiving AZT vs. SOC patients reciving AZT.‡P=.001 for epoetin alfa-treated patients not receiving AZT vs. SOC patients not receiving AZT.

P-45

PRESCO trial: designPRESCO trial: design

Study weeks

0 96724824 60 84

PE

GA

SY

S® 1

80 µ

g p

lus

CO

PE

GU

S®

1000

–120

0 m

g

12 36

Follow-up

G2,3

G1,4

G1,4

G2,3

Follow-up

Follow-up

Follow-up

Patients who achieved EVR (>2 log10 drop in HCV RNA at week 12) continued treatment

n=398

P-46

Presco ResultsPresco Results

P-47

Follow-up

US study in HIV–HCV co-infected NR to US study in HIV–HCV co-infected NR to IFN ± RBV (Dieterich, Sulkowski)IFN ± RBV (Dieterich, Sulkowski)

Study weeks

24 1200 48

NR

to

IFN

or

IFN

/RB

V, n

=10

0

72 96

HCV RNA pos

HCV RNA n

eg

Follow-up

Peg-IFNα-2a 90 µg

Follow-up

Peg-IFNα-2a 180 µg plus

RBV 800–1200 mg

Peg-IFNα-2a 180 µg plus

RBV 1200 mg

No treatment

Randomisation

P-48

Untreated Follow-up

SLAM-C trial in HIV–HCV co-infected SLAM-C trial in HIV–HCV co-infected non-responders (Sherman)non-responders (Sherman)

Peg-IFNα-2a 180 µg plus

RBV 800–1200 mg

HCV RNA 2 log dropNR and

naïve n=200

HCV RNA

<2 log drop12 weeks

Peg-IFNα-2a 180 µg plus

RBV 800–1200 mg

Peg-IFNα-2a 180 µg

Stop treatment, observation period

60 weeks

72 weeks

24 weeks

Randomisation

P-49

Approach to non-respondersApproach to non-responders

METAVIR 0METAVIR 0––11 Wait for new Wait for new

treatment treatment options options (Helicase, (Helicase, protease protease inhibitors, inhibitors, polymerase polymerase inhibitors)inhibitors)

METAVIR 2METAVIR 2––33 Retreat with Retreat with

Peg-IFN + RBVPeg-IFN + RBV Consider Peg Consider Peg

360 and wt 360 and wt based RBVbased RBV

Treat with Treat with insulin insulin sensitizersensitizer

METAVIR 3METAVIR 3––44 Retreat with Retreat with

Peg-IFN + RBVPeg-IFN + RBV Antifibrotic Antifibrotic

treatment treatment strategystrategy

Consider Peg Consider Peg 360 and wt 360 and wt based RBVbased RBV

Treat with Treat with insulin insulin sensitzersensitzer

Liver biopsy

P-50

Orthotopic Liver TransplantationOrthotopic Liver Transplantation

23 HIV + compared to UNOS 23 HIV + compared to UNOS (11,453 HIV -)(11,453 HIV -)

HCV, 14 and HBV, 9HCV, 14 and HBV, 9 CD4, 200 (range 76 – 506)CD4, 200 (range 76 – 506) MELD 16 MELD 16

HCV worse than HBVHCV worse than HBV Drug-drug interaction Drug-drug interaction

(tacrolimus)(tacrolimus) Outcome not associated Outcome not associated

with HIV RNA or CD4with HIV RNA or CD4

Survivial after OLT

70

80

90

100

12 24 36

Months%

HIV negative HIV positive

Ragni M. Survival in HIV-infected Liver Transplant Recipients. 10th CROI #155

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Nelfinavir: interaction with tacrolimusNelfinavir: interaction with tacrolimus

Mean 38-fold tacrolimus dose reduction for Mean 38-fold tacrolimus dose reduction for patients taking nelfinavir compared to patients taking nelfinavir compared to placeboplacebo

Mean dose for patients (n = 5) on nelfinavir: Mean dose for patients (n = 5) on nelfinavir: 0.26mg/d 0.26mg/d

Frequent drug level monitoring and great Frequent drug level monitoring and great caution are necessary when introducing or caution are necessary when introducing or withdrawing HAART in HIV-positive organ withdrawing HAART in HIV-positive organ transplant recipientstransplant recipients

Jain et al. Liver Transpl. 2002;8:841-845

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Patient SurvivalPatient Survivalcompared with OPTNcompared with OPTN

 

One Year Patient Survival

 

Three Year Patient Survival

 

All OPTN 87.6(87.0, 88.2)

 

95.6(95.4, 95.8)

  79.9(79.3, 80.5)

90.8(90.5, 91.1)

65 years+ OPTN 80.5(77.9, 83.0)

 

90.4(89.4, 91.3)

  69.6(66.9, 72.2)

78.0(76.6, 79.4)

HIV-infected study subjects

90.9(73.9, 100)

93.8(81.9, 100)

  80.8(56.8, 100)

93.8(81.9, 100)

 

Liver Kidney

 

Liver Kidney

Based on OPTN data as of February 4, 2005.

One year survival is based on 1999 - 2001 transplants, and 3 year survival is based on 1996 - 1999 transplants.

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Participating CentersParticipating Centers(visit the study website for updated list of centers and contact information) (visit the study website for updated list of centers and contact information)

   Atlanta Emory University (K)

Baltimore University of Maryland (K)Boston Beth Israel Deaconess Medical Center (K, L)

Charlottesville University of Virginia (K, L)Chicago University of Chicago (K, L, Peds K, Peds L)

Cincinnati University of Cincinnati (K, L)Cleveland Cleveland Clinic (K, L)

Los Angeles Cedars-Sinai (L)Miami University of Miami (K)

New Orleans Tulane (K, L)New York Mount Sinai School of Medicine (K, L, Peds K)New York Columbia University (L, Peds L)

Philadelphia Drexel University (K)Philadelphia University of Pennsylvania (K, L)

Pittsburgh University of Pittsburgh (K, L)San Francisco University of California (K, L, Peds K, Peds L)

Washington, D.C. Washington Hospital Center (K)Washington, D.C. Georgetown Medical Center (K, L)

Chicago Rush University (K, L)

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ConclusionsConclusions

HCV is a major, if not the major cause of HCV is a major, if not the major cause of morbidity and mortality in HIV+ patients morbidity and mortality in HIV+ patients todaytoday

Successful treatment of HCV (cure) in Successful treatment of HCV (cure) in HIV+ patients is possible and even likely HIV+ patients is possible and even likely with pegylated interferon and ribavirinwith pegylated interferon and ribavirin

Side effects can be effectively managed to Side effects can be effectively managed to ensure treatment successensure treatment success

Liver (and kidney) transplant is possible Liver (and kidney) transplant is possible and is being investigated in HIV+ patientsand is being investigated in HIV+ patients

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For more information, please visit www.virology-education.com

• Acute Hepatitis C- epidemiology and treatment • Chronic Hepatitis C- kinetics, current treatment

and new therapies• Hepatitis B - Treatment strategies• Liver Transplantation- selection and management• Steatosis in HIV and HCV• Non invasive measures of fibrosis• End stage of liver disease managment• Tayloring ART therapy in Hepatitis• Update on new drugs for HCV and HBV• Clinical cases

Topics

Registration:

Early reg. Feb. 15 - March 15, 2007

Regular reg. March 16 - April 30, 2007

Late reg. May 1 - May 31, 2007

Abstract submission:

Deadline April 30, 2007

More information

Timelines