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Hepatitis C virus Treatment

Hepatitis C virus Treatment. Ermias D (MD). 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,

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Hepatitis C virus Treatment

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  1. Hepatitis C virus Treatment Ermias D (MD)

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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 ??

  18. 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

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

  20. 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

  21. thank you

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