HCV Treatment Failure

(1)

ﻢﻴﺣﺮﻟا ﻦﻤﺣﺮﻟا ﷲا ﻢﺴﺑ

(2)

HCV Treatment Failure

Gamal

Esmat

PROF.OF HEPATOLOGY&TROPICAL MEDICINE

CAIRO UNIVERSITY

Director of Viral Hepatitis Treatment Centers (

Director of Viral Hepatitis Treatment Centers (VHTCsVHTCs)) MOH

MOH--EGYPTEGYPT

www.gamalesmat.com

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Determinants OF RESPONCE

Viral

Factors:(Genotype

,, Viral load,

Quaisespecies

)

Drug Factors : (Type of INF , Dose, Duration)

Patient Factors:

Age, Sex, Ethnicity

Infections (HIV,HBV,

Schistosomiasis

)

Metabolic ( D.M, Weight, BMI)

Liver histopathology (Cirrhosis ,

(6)

Predictors of Treatment Failure

O Genotype

O High pre-treatment HCV RNA O Advanced fibrosis

O BMI >30 O Age >60

(7)

(8)

Effect of baseline viral load in HCV

-

4

4 patients

patients

67 21 13 48 14 38 0 100 SVR Relapse Non-responder

HCV RNA at baseline <600,000, IU/ML (n=24) HCV RNA at baseline ≥600,000, IU/ML (n=21)

Huepper et al, Hepatology 46 (4S): 389A, Abstract 336

(9)

Predictors of SVR

Viral Load

57 78 65 38 45 42 0 20 40 60 80 100 P er cen ta g e ≤10*5 >10*5 <105 18% >105 82%

INF Alfa-2b PEG-INF Total

>105 _<105

P = 0.1

P = 0.2

By COBAS Amplicor HCV RNA 2.0 Assay Measured by IU / ML

(10)

Liver biopsy : METAVIR scoring system

F1 F2 F3 F4

From Z. Goodman From Z. Goodman

(11)

Cirrhosis

The presence of portal fibrosis or cirrhosis is

independently associated with decreased SVR

rates (Wright, 2002).

The use of interferon in patients with cirrhosis

has been limited by concerns regarding

adverse effects, particularly myelosuppression

that can lead to clinically significant

thrombocytopenia or neutropenia (Heathcote,

2000).

(12)

SVR rates and impact of fibrosis in

patients with HCV

-

4

65 46.6 46.4 21.2 36 27.3 0 100 F0 - F1 - F2 F3 - F4 Egyptian French African p=0.01 Fibrosis score SVR (%) •

pegIFNα-2b (1.5 μg / kg / week) plus RBV (1,000 – 1,200 mg / day) for 48 weeks

(13)

Impact of cirrhosis on SVR in

Chronic Hepatitis

43.4 21 57.7 21 0 20 40 60 80 P er cen tag e

IFN Alfa-2b PEG-IFN Alfa-2b

Cirrhosis 14% No Cirrhosis 86% Cirrhosis No Cirrhosis

(14)

(15)

(16)

Predictors of SVR

Body Mass Index

47.6 54.2 51.1 33.3 37.2 35 0 20 40 60 80 100 P er cen tag e <30 >30

IFN Alfa-2b PEG-IFN Alfa-2b Overall

>30 31% <30 69% >30 <30 Kg/m2 P = 0.2 P = 0.2 _{P = 0.08}

(17)

Predictors

of

treatment

failure

In univariate analysis:

Weight > 80 kg

METAVIR score ≥ F3 Steatosis

AFP levels > median value

In multivariate analysis:

AFP levels only

(18)

AFP

analysis

• Median (range) serum AFP level was 4.5 (1.2 – 49.8)

ng/mL

• Overall SVR rate was 61.0% (61/100):

– 80.4% in those with AFP ≤ 4.5 ng/ml – 40.8% in those with AFP > 4.5 ng/ml

• None of the 7 patients with AFP pretreatment > 15

ng/mL achieved SVR

(19)

SVR (%) according to the

Metavir

fibrosis score and median AFP values

43 39 75 81 0 10 20 30 40 50 60 70 80 90 100 F1 or F2 F3 or F4

Light grey:

AFP ≤ 4.5 ng/ml

Dark grey:

AFP > 4.5 ng/ml

(20)

•

• Among genotype 4

Among genotype 4

cronic

hepatitis C patients,

severe fibrosis,

severe

steatosis

,

treatment with standard interferon and

a high serum AFP level

were all

negatively

associated with SVR.

Pretreatment serum AFP level should be

considered in the routine assessment

of factors predictive of a treatment response.

Liver Int.,2008

(21)

♦

Trematode parasitic

infection

♦

Intermediate host:

water snails

♦

Debilitating disease,

severity depends on

“worm load”

Theodor Bilharz (1825-1862) first described the trematode working at Kasr El Ainy hospital in Cairo

in 1851

(22)

Is schistosomal infection has an influence on

anti-viral therapy?

EL-Shazly et al., (1994); reported

low rate of

response

in combined infection than in HCV

alone.

The presence of associated schistosomiasis has

determined the response of Egyptians with

chronic hepatitis C to therapy with interferon

(Abdel Basset et al., 1994).

(23)

THo IL-2 IFN-γ IL-4 IL-5 IL-10 Th2 IL-4 IL-5 IL-10 + + +

Viral

clearance

IL-2 IFN-γ Th1 + + + Immunopathogenesis of Combined infection

(24)

Immunopathogenesis of

Combined Infection

Schistosomiasis appears to

induce Th2 cytokine

profile, with ↑ IL-4, IL-10. It

downregulate

the

stimulatory effect of HCV on

Th1 cytokines

and this

may lead to chronicity of HCV infection in

coinfected patients (El-Kady et al., 2004& 2005).

(25)

Predictors of Treatment Failure

O Genotype

O BMI >30 O Age >60

Poor Adherence to therapy?

(26)

0 20 40 60 80 100 Genotype 1 Genotype 2 or 3 ITT 80/8 0/80 <80/ <80/ >80 SVR (%) PEG-IFN α-2b 1.5 μg/kg/wk + RBV 800 mg/day x 48 wks McHutchison JG et al. Gastroenterology 2002;123:1061-1069.

<80/ <80/ >80 80/8 0/80 ITT 88% 94% 95% 48% 63% 34% n=122 n=63 n=32 n=58 n=32 n=19

Impact of Adherence on HCV Response

Rates: PEG-IFN + RBV and 80/80/80

(27)

Drug Discontinuation Significantly

Compromises SVR Rates

75 67 12 67 56 7 0 10 20 30 40 50 60 70 80 All Genotype 1 Full Dose Dose Reduced Early Discontinuation

Fried et al, N Engl J Med, 2002

PEG-IFN α- 2a 180 μg qwk + RBV 1000-1200 mg

(28)

Both

Doses ≥80% RBV Dose <80%;PEG Dose ≥80% Treatment Factor

PEG Dose <80%;

RBV Dose ≥80% Doses <80%Both

Davis GL et al. Hepatology 2003;38:645-652.

80% 80% 70% 70% 60% 60% 33% 33% <80% ≥80% 0 50 75 Chance of EVR (%) 25

100 PEG-IFN α-2b start dose: 1.5 μg/kg each week

RBV start dose: 800 mg/d

n=324 n=38 n=3 n=15

Adherence During First 12 Wks of PEG-IFN

α-2b +

RBV Therapy Affects Early Virologic Response

(29)

Adherence: Take-home Messages

O

Adherence critical for SVR

– Discontinuations have major impact on SVR

O

Adherence in first 12 weeks of treatment

affects EVR

O

Reasons for lack of adherence:

– Lack of patient education – Lack of support system

(30)

(31)

PEG Interferon/Ribavirin

Side Effect Profile

z Headache 62% z Fatigue 66% z Myalgia 56% z Anorexia 32% z Nausea 43% * z Diarrhea 22% z Anxiety 47% z Depression 31%

z Insomnia 40% *> 10% difference from interferon/ribavirin

z Cough 23% z Dyspnea 26% z Pharyngitis 12% z Alopecia 36% z Pruritus 29% z Rash 24% z Fever 46%* z Inj Site Rxn 75%*

(32)

Time Course of Interferon Side

Effects

Severity Flu-like symptoms Fatigue Depressive/anxiety symptoms IFN Treatment (Weeks) 0 2 4 6 8 10 12

(33)

Side Effect Management

General Strategies

O GOAL: Encourage patient adherence to

treatment regimen

O Patient education about expectations O Patient self-management techniques

O Regular follow-up visits in a supportive environment

– Permits early detection of emerging AE – Permits early intervention when needed

(34)

O Most adverse events are mild to moderate

regardless of therapy

O Dose discontinuation appears to increase with

longer therapy (48 vs 24 weeks)

O Patients can achieve expected response rates only if

they can adhere to treatment

O Side effect management strategies can improve

outcome and QOL

(35)

Predictors of Treatment Failure

O Genotype

O BMI >30 O Age >60

O AFP

O Schistosomiasis

Poor Adherence to therapy?

(36)