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IFN a-2a 6/3 MIU. PEGASYS™ 180 µg. Standard Interferon vs. Pegylated Interferon. * P < 0.001. 69%*. 80. 70. 60. 39%*. Response (%). 50. 40. 28%. 30. 19%. 20. 10. 0. Sustained. End of treatment. * Intent-to-treat population. Standard Interferon vs. Pegylated Interferon.

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standard interferon vs pegylated interferon

IFN a-2a 6/3 MIU

PEGASYS™ 180 µg

Standard Interferon vs. Pegylated Interferon

* P < 0.001

69%*

80

70

60

39%*

Response(%)

50

40

28%

30

19%

20

10

0

Sustained

End of treatment

*Intent-to-treat population

Adeel A. Butt, MD

slide2

Standard Interferon vs. Pegylated Interferon

Genotype 1

40

28%

30

Patients with Response (%)

20

7%

10

0

IFN -2a

PEG -IFN

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

Adeel A. Butt, MD

standard interferon vs pegylated interferon3
Standard Interferon vs. Pegylated Interferon

Genotype 2,3

56%

60

50

37%

40

Patients with Response (%)

30

20

10

0

IFN-2a

PEG -IFN

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

Adeel A. Butt, MD

peg alone vs ifn rbv vs peg rbv
PEG alone vs. IFN+RBV vs. PEG+RBV

PEG-IFN -2a

+ Placebo

(n = 224)

IFN -2b

+ RBV

(n = 444)

PEG-IFN -2a

+ RBV

(n = 453)

Age (mean, y) 42.3 42.4 42.8

Male Gender68% 73% 71%

Weight (kg) 78.9 78.1 79.6

Genotype

1 64% 64% 66%

2 and 3 31% 33% 31%

HCV RNA Titers

(mean, 106 c/mL) 5.9 6.0 6.1

Cirrhosis 15% 12% 12%

Adeel A. Butt, MD

Fried MW et al. NEJM 2002

peg alone vs ifn rbv vs peg rbv sustained virologic response
PEG alone vs. IFN+RBV vs. PEG+RBVSustained Virologic Response

P = 0.001 for all comparisons

56%

60%

n = 453

45%

40%

n = 444

30%

% Patients

n = 224

20%

0%

IFN -2b

+ RBV

PEG-IFN -2a

+ Placebo

PEG-IFN -2a

+ RBV

Adeel A. Butt, MD

Fried MW et al. NEJM 2002

peg alone vs ifn rbv vs peg rbv sustained virologic response by genotype

P = 0.001

P = 0.001

P = 0.001

P = 0.054

P = 0.016

P = 0.008

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

80

76%

70

61%

60

% of Patients

46%

45%

50

n = 140

37%

40

n = 298

n = 145

30

n = 69

21%

n = 285

20

n = 145

10

0

Genotype 1

Genotype 2, 3

PEG-IFN -2a + PlaceboIFN -2b + RBV

PEG-IFN -2a + RBV

Adeel A. Butt, MD

ifn rbv vs low dose peg rbv vs high dose peg rbv
IFN+RBV vs. Low Dose PEG+RBV vs. High Dose PEG+RBV

80

P = .01

P = .73

60

54

47

47

SVR (%)

40

20

(n = 505)

(n = 514)

(n = 511)

0

PEG (12 kDa) IFN

alfa-2b1.5 / 0.5 g/kg+ RBV 1000-1200 mg

PEG (12 kDa) IFN

alfa-2b

1.5 g/kg+ RBV 800 mg

IFN alfa-2b 3 MIU

TIW + RBV

1000-1200 mg

Adeel A. Butt, MD

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

side effects of ifn
Flu-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

Side Effects of IFN

Adeel A. Butt, MD

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

14

13

13

14

12

10

8

Percent

6

4

2

0

IFN

alfa-2b

+ RBV

PEG IFN

alfa-2b (12 kDa)

1.5 µg/kg + RBV

PEG IFN

alfa-2b (12 kDa)

1.5/0.5 µg/kg + RBV

Adeel A. Butt, MD

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

hcv and hiv similarities
HCV and HIV - Similarities

HCV

HIV

  • + 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.

Adeel A. Butt, MD

hcv and hiv
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
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

80

60

Deaths Due to Liver Disease

(O/E)

40

20

0

HIV+

HIV-

GP

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

Adeel A. Butt, MD

increasing mortality from esld in patients with hiv
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

50

40

30

20

10

0

50

1991

1996

1998

ESLD-Related Deaths (%)

14

11

ESLD = end stage liver disease;

NDVL = no detectable viral load.

Adeel A. Butt, MD

hcv hiv co infection17
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

Adeel A. Butt, MD

Soto, J Hepatol 1997;26:1-5

hcv hiv co infection18
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;172:1503-8

Staples Clin Infect Dis 1998;29:150-4

Sulkowski JAMA 2002

More AIDS at baseline

More progression

Decreased CD4 recovery

Greub, Lancet 2002

De Luca, Archives 2002

HCV-HIV Co-infection

Effect of HCV on HIV Progression

CONTROVERSIAL

Adeel A. Butt, MD

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

IFN + RPEGIFN + R

n=67 n=66p value

Overall Wk 24 VR* 10 (15%) 29 (44%) 0.0003

genotype 1** 4/52 (7%) 17/51 (33%) 0.0014

genotype non-1** 6/15 (40%) 12/15 (80%) 0.06

biochemical response 44% 54% NS

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

IFN + RPEGIFN + R

n=67 n=66 p value

Virologic nonresponders 57 (85%) 37 (56%) 0.0003

Wk 24 Bx obtained 37 23

Histologic response 15 (40%) 6 (26%) 0.28

Combined virologic and histologic response

VR + HR 25 (37%) 35 (53%) 0.08

Slide courtesy of R. Chung

Adeel A. Butt, MD

grade 4 events
Grade 4 events

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

  • Grade 0-1 18 9 NS
  • Grade 2 25 18 NS
  • Grade 3 20 22 NS
  • Grade 4 4 17 0.0012
    • ANC (< 500) 3 7 NS
    • gluc (> 500) 0 4 NS
    • plt (< 20K) 0 1 NS
    • LFTs (> 10x ULN) 0 2 NS
    • depression 1 0 NS
  • Premature D/C 8 (12%) 8 (12%) NS

Adeel A. Butt, MD

Slide courtesy of R. Chung

absolute cd4 fell but cd4 rose
Absolute CD4 fell but CD4% rose

IFN + RPEGIFN + R p value

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 0.10

DCD4 W0-24 -112 -194 0.01

D%CD4 W0-24* +2.5% +3.5% 0.14

*overall +3.0%, p = 0.0001

Slide courtesy of R. Chung

Adeel A. Butt, MD

there was no adverse effect on hiv 1 control
There was no adverse effect on HIV-1 control

HIV RNA Total IFN + RPEGIFN + Rn = 119n = 62 n = 57p

W0 W24

und und 59 (50%) 32 (52%) 27 (47%) NS

und det 9 (8%) 6 (10%) 3 (5%) NS

det und 16 (13%) 6 (10%) 10 (5%) NS

det det 35 (29%) 18 (29%) 17 (30%) NS

W0 undetectable 38 (62%) 30 (52%) NS

W24 undetectable 38 (62%) 37 (65%) NS

Slide courtesy of R. Chung

Adeel A. Butt, MD

hcv hiv co infected patients
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 patients25
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
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 ULN

Sulkowski, JAMA 2000;283:74-80.

Adeel A. Butt, MD

managing depression
Managing Depression
  • 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

Adeel A. Butt, MD

slide28

Management of Neutropenia

  • 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

Adeel A. Butt, MD

GCSF = granulocyte-colony stimulating factor.

management of rbv induced anemia
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
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

Adeel A. Butt, MD

ad