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Page 1: Hepatitis C virus Treatment

Hepatitis C virus Treatment

Ermias D (MD)

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Over view• 1989 – first case of documented HCV treatment

with interferon α– 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 IFNα (48wk) - initial response 40%, sustained

response <20%, specially for genotype 1• INFα + ribavirin – increased sustained response from 16 to

40%• Two large prospective trials showed

– HCV genotype 2 or 3; low viral loads – required 24 wks of tx for optimal outcome

– Genotype 1 and high viral load required 48 wks for optimal outcome• Genotype and pretx viral load determine duration of tx • At 24wks PCR HCV RNA – if positive dc tx - no tx response• Genotype 2 and 3, with negative PCR Viral RNA can stop tx

at 24 wks• Other genotypes and negative PCR assay need additional 24

wks tx

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Compared to HBV

• HCV tx – No transient acute hepatitis – ALT fall precipitously during tx– 90% virologic response seen in first 12 wks– Durable virologic response for 5-6yrs in

successful tx, normal ALTand improved histology ----- almost cure

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Good prognosis• Low baseline viral load < 2million c/ml• Histologically mild hepatitis, minimal fibrosis• Favorable genotype 2, 3 than 1, 4• Age <40 yrs• Non obese• Female• White population• >80% adherance• Brief duration of infection• Low HCV quasispecies diversity• Immunecompetence• Low liver iron level

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Interferon α• 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 α 3million IU sc 3X/wk before bed time

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Adverse effects of Tx• INFα• 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 <75Kg in two divided doses• Hemolysis, anemia (ACS, stroke), teratogenic• Nasal, chest congestion, pruritis, ppt gout

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contraindications• Absolute• Pregnancy, lactation, allergy to the drugs

• Relative• Decompensated cirrhosis• Bilirubin >1.5mg/dl• PT > 15sec• INR >1.7• Albumin <3.4g/dl• Ascites• Bleeding esophageal varices• Hepatic encephalopathymajor neuropsychiatric disease• Coronary or CVD• Renal failure• Solid organ transplant• Recent alcohol abuse• Anemia, leukopenia, thrombocytopenia

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Pegylated interferon

• Polyethylene glycol attachment to INFα• Extended half life, given once a wk• Dose depend on wt• Higher response rate than the

conventional tx with INF α + ribavirin• Peg INF-α 2a and 2b • Comparable efficacy, • INF α 2a well tolerated

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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 α

– 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 α +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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