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Hepatitis C virus Treatment Ermias D (MD)

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Over view 1989 first case of documented HCV treatment with interferon Normalization of ALT, but high rate of relapse interferon and ribavirin Favorable response, but still in less than half Measure of treatment success Biochemical, virologic, histologic Evaluation period: end of tx response, sustained tx response

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Acute infection Justification to tx Tx gives sustained virologic response in > 85% With out tx high rate of progression to chronic phase Limited efficacy of tx in chronic infection Drawbacks High rate of side effects Optimal tx regimen ? --- like the chronic Best point of intervention ? Diagnosing acute infection

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Supportive care hospitalization for severe illness Restrict physical activity High calorie diet Cholestatic and hepatotoxic drugs should be avoided Cholestyramine for severe pruritis Glucocorticoids no value Physical isolation/handling care bleeding patients Discharge as sx regress and decreasing trend of enzymes Fulminant cases hemodynamic support, electrolyte balance, glycemic control, control of bleeding, coma care, lactulose/neomycine, low protein, Extracorporal liver assist device liver transplantation

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Chronic infection All pts may warrant tx Clear indication Chronic HCV infection with detectable HCV RNA (10-50IU) Elevated amino transferase enzymes (N not excluded) Histologic evidence of progressive liver disease more than portal fibrosis stage (Ishak or Metavir) No additional serious coexisting condition or contraindication for tx Eradication of virus is associated with improvement in quality of life even in the absence of liver disease Decreased ds progression from compensated - decompensated cirrhosis HCC combination tx > monotx Decompensated cirrhosis unlikely to respond

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Regimens Monotx with IFN (48wk) - initial response 40%, sustained response

Good prognosis Low baseline viral load < 2million c/ml Histologically mild hepatitis, minimal fibrosis Favorable genotype 2, 3 than 1, 4 Age 80% adherance Brief duration of infection Low HCV quasispecies diversity Immunecompetence Low liver iron level

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Interferon Cytokine Attach on cell surface receptor Signal Janus activated kinase and signal transducers and activate transcription, induction of genes Double stranded RNases, viral protein inhibitors, destabilisers of viral messanger RNA Immune response genes activation of natural killer cells, maturation of dendritic cells, proliferation of memory T cells, prevention of T cell apoptosis Increased drug dose and rapid infected hepatocyte death is related to rapid viral clearance INF 3million IU sc 3X/wk before bed time

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Adverse effects of Tx INF Muscle ache, fatigue, depresion, anxiety, irritability, sleep disturbance, concentration difficulty Autoimmune rxn thyroiditis, alopecia, rashes, diarrhea, numbness Serious side effects permanent injury and death 1-2% from combination Pt information and monthly check ups sx and cbc 30-40% require dose reduction, 20% discontinuation

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ribavirin Oral nucleoside analogue Mech against HCV not clear Minimal direct activity Lead to rapid and lethal mutation of virions Depletion of intracellular guanosine triphosphase necessary for viral RNA synthesis Has immune modulatory effects Dose - 1200mg for >75Kg/ - 1000mg for

contraindications Absolute Pregnancy, lactation, allergy to the drugs Relative Decompensated cirrhosis Bilirubin >1.5mg/dl PT > 15sec INR >1.7 Albumin

responses Sustained virologic response 75-80% in genotype 2 and 3, 40-50% in genotype 1, lower response among blacks than white (28 vs 52%), poor response in initial high viral load >600,000iu/ml, male, obese, advanced liver fibrosis Transient virologic response, relapse 20%, breakthrough 10% Reappearance of HCV RNA, rise in ALT, common with short coarse tx and monotherapy Non response HCV RNA remain detectable and ALT remain raised Common with genotype 1 (30%), rare in genotypes 2, 3.

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Tx of ribavirin contraindication PegINF Also for 20% of pt who after combination tx develop ribavirin induced anemia Retreatment Relapse or non response after standard INF monotx or with ribavirin PegIFN +Ribavirin Tx for non responders to PegIFN +Ribavirin no available tx, need controlled clinical trials. High dose IFN induction, amantadine, maintenance tx,.. Maintenance tx Cutaneous vasculitis, GN ass with HCV ?? Relapses, non responses

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Areas of uncertainity Tx for children Tx acute hepatitis C >85% virologic response if tx initiated in 6 months time Or 75% progress to chronic phase High side effects in acute tx Improving side effects and cost (30-40,000USD) Futile to continue tx in genotype 1 if RNA positive at 24wk Prediction If no 2log10IU/ml viral drop or undetectable by 12 wk --- 98-100% non response Rapid response HCV RNA negative by 4 wk, dc at 12-16 wk for genotype 2, 3 and at 24 for genotype 1 and low level HCV RNA

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Liver transplant For decompensated HCV related cirrhotic pts, and early stage HCC Reinfection of graft inevitable Accelerated disease progression (in immuno suppressed) Pre and post transplant viral suppression, New tx needed Similar 1 and 5 yr survival rate with other liver transplant cases ??

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Co infection with HIV1 Increased risk of disease progression Tx early regardless of ALT, histology Poor rates of response to monotherapy like HCV infection alone Similar efficacy as a lone HCV with combination tx HAART immune reconstitution, hepatotoxic drugs exacerbate hepatitis Initiat tx for HCV before HAART

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Potential target for future drug development HCV proteases helicase Polymerase Internal ribosomal entry site Putative cell surface receptor CD81 Newer INF

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prevention Ineffective Ig, vaccine - - immunoprophylaxis not feasible Chemoprophylasis none Universal precautions Screening transfusion blood and blood products Sterile interventional materials Avoid sharing razor blade, nail clippers. Avoid multiple sexual partnership, use barriers No fear in stable monogamous sexual partners No special precaution for babies from infected mothers No restriction of breast feeding

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