HCV Treatment Failure

بسم االله الرحمن الرحيم

HCV Treatment Failure Gamal Esmat PROF.OF HEPATOLOGY&TROPICAL MEDICINE CAIRO UNIVERSITY Director of Viral Hepatitis Treatment Centers (VHTCs( VHTCs) MOH-EGYPT www.gamalesmat.com

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,Steatosis,Iron, Steatosis,Iron)

Predictors of Treatment Failure Genotype High pre-treatment HCV RNA Advanced fibrosis BMI >30 Age >60

Effect of baseline viral load in HCV-4 patients 100 Patients (%) 67 HCV RNA at baseline <600,000, IU/ML (n=24) HCV RNA at baseline 600,000, IU/ML (n=21) 48 21 14 13 38 0 SVR Relapse Non-responder Huepper et al, Hepatology 46 (4S): 389A, Abstract 336

Predictors of SVR Viral Load 100 P = 0.2 P = 0.1 P = 0.04 Esmat et al, UEGW, 2003, Madrid Percentage 80 60 40 57 78 65 38 45 42 >10 5 82% <10 5 18% 20 0 10*5 >10*5 INF Alfa-2b PEG-INF Total >10 5 <10 5 By COBAS Amplicor HCV RNA 2.0 Assay Measured by IU / ML

Liver biopsy : METAVIR scoring system F1 F2 F3 F4 From Z. Goodman

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).

SVR rates and impact of fibrosis in patients with HCV-4 100 65 SVR (%) 46.4 36 46.6 21.2 27.3 Egyptian French African 0 p=0.01 F0 - F1 - F2 Fibrosis score F3 - F4 pegifnα-2b (1.5 μg / kg / week) plus RBV (1,000 1,200 mg / day) for 48 weeks Roulot et al, J Viral Hepat 2007; 14: 460

Impact of cirrhosis on SVR in Chronic Hepatitis 80 Cirrhosis 14% 60 57.7 Percentage 40 20 43.4 21 21 No Cirrhosis 86% Cirrhosis No Cirrhosis 0 IFN Alfa-2b PEG-IFN Alfa-2b Esmat et al, UEGW, 2003, Madrid

Predictors of SVR Body Mass Index IFN Alfa-2b PEG-IFN Alfa-2b Overall 100 P = 0.2 P = 0.2 P = 0.08 Percentage 80 60 40 47.654.2 51.1 33.3 37.2 35 <30 69% >30 31% 20 0 <30 >30 >30 <30 Kg/m 2

Predictors of treatment failure In univariate analysis: Weight > 80 kg METAVIR score F3 Steatosis AFP levels > median value In multivariate analysis: AFP levels only Antiviral Therapy,2007,12:797

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 Antiviral Therapy,2007,12:797

SVR (%) according to the Metavir fibrosis score and median AFP values 100 90 80 70 60 81 75 Light grey: AFP 4.5 ng/ml 50 40 30 20 43 39 Dark grey: AFP > 4.5 ng/ml 10 0 F1 or F2 F3 or F4

Liver Int.,2008 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.

Schistosomiasis 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

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).

+ + + Th1 IL-2 IFN-γ Viral clearance THo IL-2 IFN-γ IL-4 IL-5 IL-10 + + + Th2 IL-4 IL-5 IL-10 Immunopathogenesis of Combined infection

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).

Predictors of Treatment Failure Genotype High pre-treatment HCV RNA Advanced fibrosis BMI >30 Age >60 Poor Adherence to therapy? A Modifiable Risk Factor!

Impact of Adherence on HCV Response Rates: PEG-IFN + RBV and 80/80/80 100 Genotype 1 Genotype 2 or 3 88% 94% 95% 80 SVR (%) 60 40 48% 63% 34% 20 0 n=122 n=63 n=32 ITT 80/80/80 <80/<80/>80 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. n=58 n=32 n=19 ITT 80/80/80 <80/<80/>80

Drug Discontinuation Significantly Compromises SVR Rates PEG-IFN α- 2a 180 μg qwk + RBV 1000-1200 mg 80 70 60 50 75 67 67 56 Full Dose SVR (%) 40 30 20 10 12 7 Dose Reduced Early Discontinuation 0 All Genotype 1 Fried et al, N Engl J Med, 2002

Adherence During First 12 Wks of PEG-IFNα-2b + RBV Therapy Affects Early Virologic Response 100 PEG-IFN α-2b start dose: 1.5 μg/kg each week RBV start dose: 800 mg/d Chance of EVR (%) 75 50 25 0 80% 80% Both Doses 80% 70% PEG Dose <80%; RBV Dose 80% <80% 60% RBV Dose <80%; PEG Dose 80% 33% n=324 n=38 n=3 n=15 Both Doses <80% Treatment Factor Davis GL et al. Hepatology 2003;38:645-652.

Adherence: Take-home Messages Adherence critical for SVR Discontinuations have major impact on SVR Adherence in first 12 weeks of treatment affects EVR Reasons for lack of adherence: Lack of patient education Lack of support system Side Effects By far the most common

No Two Patients Are Alike

PEG Interferon/Ribavirin Side Effect Profile Headache 62% Fatigue 66% Myalgia 56% Cough 23% Dyspnea 26% Pharyngitis 12% Anorexia 32% Nausea 43% * Diarrhea 22% Anxiety 47% Depression 31% Alopecia 36% Pruritus 29% Rash 24% Fever 46%* Inj Site Rxn 75%* Insomnia 40% *> 10% difference from interferon/ribavirin

Time Course of Interferon Side Effects Severity Flu-like symptoms Fatigue Depressive/anxiety symptoms 0 2 4 6 8 10 12 IFN Treatment (Weeks)

Side Effect Management General Strategies GOAL: Encourage patient adherence to treatment regimen Patient education about expectations Patient self-management techniques Regular follow-up visits in a supportive environment Permits early detection of emerging AE Permits early intervention when needed Ideal utilization of trained physicians

Side Effect Management Most adverse events are mild to moderate regardless of therapy Dose discontinuation appears to increase with longer therapy (48 vs 24 weeks) Patients can achieve expected response rates only if they can adhere to treatment Side effect management strategies can improve outcome and QOL

Predictors of Treatment Failure Genotype High pre-treatment HCV RNA Advanced fibrosis BMI >30 Age >60 AFP Schistosomiasis Poor Adherence to therapy? A Modifiable Risk Factor!

Thank you gesmat@gamalesmat.com