Adeel A. Butt, MD

* P < 0.001

0

10

20

30

40

50

60

80

28%

69%*

70

End of treatment

Sustained

39%*

19%

IFN a-2a 6/3 MIUPEGASYS™ 180 µg

Response(%)

Standard Interferon vs. Pegylated Interferon

* Intent-to-treat population

Adeel A. Butt, MDZeuzem et al. NEJM 2000; 343:1666-1672

Standard Interferon vs. Pegylated Interferon

0

10

20

30

40

Patie

nts w

ith R

espo

nse

(%)

7%

28%

IFN -2a PEG -IFN

Genotype 1

Adeel A. Butt, MD

0

10

20

30

40

50

60

Patie

nts w

ith R

espo

nse

(%)

37%

56%

IFN-2a PEG -IFN

Zeuzem et al. NEJM 2000; 343:1666-1672

Standard Interferon vs. Pegylated Interferon

Genotype 2,3

Adeel A. Butt, MD

IFN IFN -2b-2b+ RBV+ RBV

(n = 444)(n = 444)

PEG-IFN PEG-IFN -2a-2a+ Placebo+ Placebo(n = 224)(n = 224)

PEG alone vs. IFN+RBV vs. PEG+RBV

PEG-IFN PEG-IFN -2a-2a+ RBV+ RBV

(n = 453)(n = 453)

Age (mean, y)Age (mean, y) 42.342.3 42.442.4 42.842.8Male GenderMale Gender 68%68% 73%73% 71%71%Weight (kg)Weight (kg) 78.978.9 78.178.1 79.679.6GenotypeGenotype 11 64%64% 64%64% 66%66% 2 and 32 and 3 31%31% 33%33% 31%31%HCV RNA TitersHCV RNA Titers(mean, 10(mean, 1066 c/mL) c/mL) 5.95.9 6.06.0 6.16.1CirrhosisCirrhosis 15%15% 12%12% 12%12%

Fried MW et al. NEJM 2002

Adeel A. Butt, MD

PEG alone vs. IFN+RBV vs. PEG+RBVSustained Virologic Response

n = 224

n = 444

n = 45330%

56%

45%

0%

20%

40%

60%

% P

atie

nts

IFN -2b + RBV

PEG-IFN -2a+ Placebo

PEG-IFN -2a+ RBV

P = 0.001 for all comparisons

Fried MW et al. NEJM 2002

Adeel A. Butt, MD

% o

f Pat

ient

s

0

10

20

30

40

50

60

70

80

Genotype 1 Genotype 2, 3

n = 285n = 298

37%

21%

46%

n = 145

n = 145n = 140

61%45%

76%

n = 69

PEG alone vs. IFN+RBV vs. PEG+RBVSustained Virologic Response by Genotype

PEG-IFN -2a + PlaceboIFN -2b + RBV PEG-IFN -2a + RBV

P = 0.001

P = 0.054 P = 0.008P = 0.001

P = 0.001 P = 0.016

Adeel A. Butt, MD

IFN+RBV vs. Low Dose PEG+RBV vs. High Dose PEG+RBV

47 4754

0

20

40

60

80

IFN alfa-2b 3 MIU TIW + RBV

1000-1200 mg

SV

R (%

)

PEG (12 kDa) IFN alfa-2b

1.5 / 0.5 g/kg+ RBV 1000-1200 mg

PEG (12 kDa) IFN alfa-2b

1.5 g/kg+ RBV 800 mg

P = .01

Manns et al. Lancet. 2001;358:958-965.

(n = 511)(n = 505) (n = 514)

P = .73

Adeel A. Butt, MD

Adeel A. Butt, MD

Side Effects of IFNFlu-like symptoms

Headache Fatigue or asthenia Myalgia, arthralgia Fever, chills

Nausea Diarrhea Alopecia Thyroiditis

Psychiatric symptoms Depression Mood lability

Injection site reaction Autoimmunity Lab alterations

Neutropenia Anemia Thrombocytopenia

Adeel A. Butt, MD

Side Effects of RBV

Hemolytic anemia Teratogenicity Cough and dyspnea Rash and pruritus Insomnia Anorexia

Rebetron [package insert]. Kenilworth, NJ: Schering Corp; 1999.

Adeel A. Butt, MD

PEG (12 kDa) IFN alfa-2b Incidence of Discontinuations Due to Adverse Events

0

2

4

6

8

10

12

1414

IFN = interferon; PEG = polyethylene glycol; RBV = ribavirin.

1313

PEG IFN alfa-2b (12 kDa) 1.5 µg/kg + RBV

PEG IFN alfa-2b (12 kDa)

1.5/0.5 µg/kg + RBV

IFN alfa-2b + RBV

Per

cent

HCV-HIV Co-infection

Adeel A. Butt, MD

HCV and HIV - Similarities

+ ssRNA – Flavivirus Virions/d = 1012

Diversity/complexity Six genotypes

Tropism: hepatocyte Receptors: LDL, CD81

+ ssRNA – Retrovirus Virions/d = 1010 - 1011

Diversity/complexity 11+ clades

Tropism: lymphoid Receptors: CD4, CCR5

HIV

CCR5 = chemokine receptor 5; CD4 = cluster of deviation 4; CD81 = cluster of deviation 81; LDL = low density lipoprotein; + ssRNA = positive single strand ribonucleic acid.

HCVHCV HIV

Adeel A. Butt, MD

HCV and HIV

Prevalence of HCV in HIV > 10x general population

Reported to be between 30-50%

~6% of VA population HCV infected

~35-43% of HIV infected veterans have HCV

Greub, Lancet 2000;356:1800-5

Adeel A. Butt, MD

Hepatitis C Virus and HIV Liver-Related Mortality

UK hemophilia population, 1985-1998

Deaths due to liver disease

• HIV - 16.7-fold• HIV + 94.4-fold

Risk after 10 years

0

20

40

60

80

HIV+ HIV- GP

GP = general population; HIV = human immunodeficiency virus; O/E = observed to expected.

Dea

ths

Due

to L

iver

Dis

ease

Dea

ths

Due

to L

iver

Dis

ease

(O/E

)(O

/E)

Adeel A. Butt, MD

Increasing Mortality From ESLD in Patients With HIV

One third of 1998 cohort had recent history of discontinuing HAART secondary to hepatotoxicity

More than 1/2 who died with ESLD had either NDVL or CD4 >200/mm3 6 months prior to death

ES

LD-R

elat

ed D

eath

s (%

)

199119961998

50

40

30

20

10

0

1114

50

ESLD = end stage liver disease; NDVL = no detectable viral load.

Adeel A. Butt, MD

HCV-HIV Co-infection

Progression of liver disease accelerated in HCV-HIV co-infected patients

Median time to cirrhosis 7 years in HCV-HIV vs. 23 years in HCV alone

Soto, J Hepatol 1997;26:1-5

11,5

75

13,9

57,750

93,8

0102030405060708090

100

1991 1996 1998-99

Deaths related toESLD% of ESLD deaths whowere HCV positive

Adeel A. Butt, MD

HCV-HIV Co-infection

Generally no increase in HIV progression

No difference in survival, progression from HIV to AIDS or AIDS to death or HIV to death

Rate of decline of CD4 counts is also similar

Dorrucci, JID 1995;172:1503-8Staples Clin Infect Dis

1998;29:150-4Sulkowski JAMA 2002

More AIDS at baseline

More progression Decreased CD4

recovery

Greub, Lancet 2002 De Luca, Archives

2002

Effect of HCV on HIV Progression

CONTROVERSIAL

Adeel A. Butt, MD

PEG-IFN + RBV is associated with a superior week 24 virologic response (VR)

Overall Wk 24 VR* 10 (15%) 29 (44%) 0.0003genotype 1** 4/52 (7%) 17/51 (33%) 0.0014genotype non-1** 6/15 (40%) 12/15 (80%) 0.06biochemical response 44% 54% NS

IFN + R PEGIFN + R n=67 n=66 p value

*intent to treat **Genotype 1 vs. non-1, p < 0.0001

Slide courtesy of R. Chung

Adeel A. Butt, MD

A significant portion of virologic nonresponders experience histologic response (HR)

Virologic nonresponders 57 (85%) 37 (56%) 0.0003Wk 24 Bx obtained 37 23Histologic response 15 (40%) 6 (26%) 0.28

Combined virologic and histologic responseVR + HR 25 (37%) 35 (53%) 0.08

IFN + R PEGIFN + R n=67 n=66 p value

Slide courtesy of R. Chung

Adeel A. Butt, MD

Grade 4 events

Grade 0-1 18 9 NSGrade 2 25 18 NSGrade 3 20 22 NSGrade 4 4 17 0.0012

ANC (< 500) 3 7 NSgluc (> 500) 0 4 NSplt (< 20K) 0 1 NSLFTs (> 10x ULN) 0 2 NSdepression 1 0 NS

Premature D/C 8 (12%) 8 (12%) NS

IFN + R PEGIFN + R n = 67 n = 66 p

value

Slide courtesy of R. Chung

Adeel A. Butt, MD

Absolute CD4 fell but CD4% rose

Wk 0 CD4 452 500 0.07%CD4 24.0 25.5 0.19

Wk 24 CD4 369 363 0.80%CD4 27.0 30.5 0.10CD4 W0-24 -112 -194 0.01%CD4 W0-24* +2.5% +3.5% 0.14

IFN + R PEGIFN + R p value

*overall +3.0%, p = 0.0001

Slide courtesy of R. Chung

Adeel A. Butt, MD

There was no adverse effect on HIV-1 control

W0 W24und und 59 (50%) 32 (52%) 27 (47%) NSund det 9 (8%) 6 (10%) 3 (5%) NSdet und 16 (13%) 6 (10%) 10 (5%) NSdet det 35 (29%) 18 (29%) 17 (30%) NSW0 undetectable 38 (62%) 30 (52%) NSW24 undetectable 38 (62%) 37 (65%) NS

HIV RNA Total IFN + R PEGIFN + R

n = 119 n = 62 n = 57

p

Slide courtesy of R. Chung

Adeel A. Butt, MD

HCV-HIV Co-infected Patients

51 patients IFN alfa 2b, 3 million units TIW PLUS

RBV 1000-1200 12 months 59% genotype 1 Cirrhosis – 55% Mean CD4 = 411

Landau. AIDS 2001;15:2149-2155.

Adeel A. Butt, MD

HCV-HIV Co-infected Patients

ETVR = 29% SVR = 21% CD4 drop at end of treatment = 51

normalized after 6 months Treatment discontinuation 29%

Landau. AIDS 2001;15:2149-2155.

Adeel A. Butt, MD

Hepatotoxicity in Co-infected Patients

May be more common in co-infected patients, esp. those on PI based regimens

However, overall risk small 88% co-infected patients on HAART had

NO toxicity Reversible in those in whom it occurred

Difficult to provide guidelines on management:

Stop or change therapy if liver enzymes > 3-5 times ULNSulkowski, JAMA 2000;283:74-80.

Adeel A. Butt, MD

Take psychiatric history for depression and mania Develop relationship with mental health providers Treat preexisting depression before starting (PEG) IFN Evaluate patients for development of depression at least

every 2 weeks after initiation of IFN therapy Mild depression – evaluate weekly Moderate depression – reduce dose of IFN; consider

psychiatric consultation PEG IFN alfa-2a: reduce to 135 µg weekly PEG IFN alfa-2b: reduce dose by 1/2

Severe depression – discontinue IFN/RBV immediately and permanently; obtain immediate psychiatric consult

Managing Depression

Adeel A. Butt, MD

Neutropenia Consider G-CSF 300 µg SC BIW or TIW No controlled trials demonstrating effectiveness Clinical experience shows this to be effective ANC <750 cells/mm3 – dose reduce IFN

PEG IFN alfa-2a: decrease to 135 µg weekly PEG IFN alfa-2b: decrease dose by 1/2

ANC <500 cells/mm3 – discontinue IFN

Management of Neutropenia

GCSF = granulocyte-colony stimulating factor.

Adeel A. Butt, MD

Management of RBV-Induced Anemia

Hemoglobin determinations pretreatment, at week 2, week 4, and as needed

If >10 g/dL: no action needed If <10 g/dL: reduce RBV dose to 600 mg daily If <8.5 g/dL: stop RBV If decreases by >2 g/dL from starting therapy:

reduce dose to 600 mg daily in patients with cardiac history Hemoglobin returns to baseline within 4 weeks after RBV is

stopped Cardiac function

Anemia may exacerbate symptoms of coronary disease and/or deteriorate cardiac function

Recommend stress test for patients aged >50 years Consider epoetin alfa 40,000 IU SC QW

Adeel A. Butt, MD

Conclusions HCV is a common disease and a frequent cause of morbidity

and mortality in the US and globally Current treatment options can eradicate/cure HCV in a

significant proportion of chronically infected patients Very few eligible patients actually receive treatment HCV co-infection is very common in the HIV infected patients Treatment is associated with significant adverse events, especially in the HCV-HIV co-infected patients Benefits of treatment should be weighed against the risks, considering the long natural history of the disease