Standard Interferon vs. Pegylated Interferon

1
Standard Interferon vs. Pegylated Interferon
P lt 0.001
69
80
70

60
39
Response()
50
40

28
30
19

20

10
0
End of treatment
Sustained
Intent-to-treat population
2
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 3431666-1672
3
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 3431666-1672
4
PEG alone vs. IFNRBV vs. PEGRBV
IFN ?-2b RBV (n 444)
PEG-IFN ?-2a Placebo (n 224)
PEG-IFN ?-2a RBV (n 453)
Age (mean, y) 42.3 42.4 42.8 Male
Gender 68 73 71 Weight (kg) 78.9 78.1 79.6 Geno
type 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
Fried MW et al. NEJM 2002
5
PEG alone vs. IFNRBV vs. PEGRBVSustained
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
Fried MW et al. NEJM 2002
6
PEG alone vs. IFNRBV vs. PEGRBVSustained
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
7
IFNRBV vs. Low Dose PEGRBV vs. High Dose
PEGRBV
80
P .01
P .73
60
54
47
47


SVR ()
40
20
(n 511)
(n 505)
(n 514)
0
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
IFN alfa-2b 3 MIU TIW RBV 1000-1200 mg
Manns et al. Lancet. 2001358958-965.
8
(No Transcript)
9
Side Effects of IFN

• Psychiatric symptoms
• Depression
• Mood lability
• Injection site reaction
• Autoimmunity
• Lab alterations
• Neutropenia
• Anemia
• Thrombocytopenia

• Flu-like symptoms
• Headache
• Fatigue or asthenia
• Myalgia, arthralgia
• Fever, chills
• Nausea
• Diarrhea
• Alopecia
• Thyroiditis

10
Side Effects of RBV

• Hemolytic anemia
• Teratogenicity
• Cough and dyspnea
• Rash and pruritus
• Insomnia
• Anorexia

Rebetron? package insert. Kenilworth, NJ
Schering Corp 1999.
11
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
IFN interferon PEG polyethylene glycol RBV
ribavirin.
12
HCV-HIV Co-infection
13
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.
14
HCV and HIV

• Prevalence of HCV in HIV gt 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 20003561800-5
15
Hepatitis C Virus and HIV Liver-Related Mortality
80

• UK hemophilia population, 1985-1998
• Deaths due to liver disease
• HIV - ? 16.7-fold
• HIV ? 94.4-fold
• Risk ? after 10 years

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.
16
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 gt200/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.
17
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 1997261-5
18
HCV-HIV Co-infection
Effect of HCV on HIV Progression CONTROVERSIAL

• More AIDS at baseline
• More progression
• Decreased CD4 recovery
• Greub, Lancet 2002
• De Luca, Archives 2002

• 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 19951721503-8
• Staples Clin Infect Dis 199829150-4
• Sulkowski JAMA 2002

19
PEG-IFN RBV is associated with a superior week
24 virologic response (VR)
IFN R PEGIFN R
n67 n66 p 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 lt
0.0001
Slide courtesy of R. Chung
20
A significant portion of virologic nonresponders
experience histologic response (HR)
IFN R PEGIFN R
n67 n66 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
21
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 (lt
500) 3 7 NS gluc (gt 500) 0 4 NS plt (lt
20K) 0 1 NS LFTs (gt 10x ULN) 0 2 NS depressio
n 1 0 NS Premature D/C 8 (12) 8 (12) NS

Slide courtesy of R. Chung
22
Absolute CD4 fell but CD4 rose
IFN R PEGIFN 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 DCD4
W0-24 2.5 3.5 0.14
overall 3.0, p 0.0001
Slide courtesy of R. Chung
23
There was no adverse effect on HIV-1 control
HIV RNA Total IFN R
PEGIFN R n 119
n 62 n 57 p
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
24
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 2001152149-2155.
25
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 2001152149-2155.
26
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 gt 3-5
  times ULN

Sulkowski, JAMA 200028374-80.
27
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

28
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 lt750 cells/mm3 dose reduce IFN
• PEG IFN alfa-2a decrease to 135 µg weekly
• PEG IFN alfa-2b decrease dose by 1/2
• ANC lt500 cells/mm3 discontinue IFN

GCSF granulocyte-colony stimulating factor.
29
Management of RBV-Induced Anemia

• Hemoglobin determinations pretreatment, at week
  2, week 4, and as needed
• If gt10 g/dL no action needed
• If lt10 g/dL reduce RBV dose to 600 mg daily
• If lt8.5 g/dL stop RBV
• If decreases by gt2 g/dL from starting
  therapyreduce 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 gt50 years
• Consider epoetin alfa 40,000 IU SC QW

30
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