Hepatitis C virus Treatment

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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, - PowerPoint PPT Presentation

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  • Hepatitis C virus TreatmentErmias D (MD)

  • Over view1989 first case of documented HCV treatment with interferon Normalization of ALT, but high rate of relapseinterferon and ribavirin Favorable response, but still in less than halfMeasure of treatment success Biochemical, virologic, histologicEvaluation period: end of tx response, sustained tx response

  • Acute infectionJustification to txTx gives sustained virologic response in > 85%With out tx high rate of progression to chronic phaseLimited efficacy of tx in chronic infectionDrawbacksHigh rate of side effectsOptimal tx regimen ? --- like the chronicBest point of intervention ?Diagnosing acute infection

  • Supportive carehospitalization for severe illnessRestrict physical activityHigh calorie dietCholestatic and hepatotoxic drugs should be avoidedCholestyramine for severe pruritisGlucocorticoids no valuePhysical isolation/handling care bleeding patientsDischarge 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 deviceliver transplantation

  • Chronic infectionAll pts may warrant txClear indicationChronic 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 txEradication of virus is associated with improvement in quality of life even in the absence of liver diseaseDecreased ds progression from compensated - decompensated cirrhosis HCC combination tx > monotxDecompensated cirrhosis unlikely to respond

  • RegimensMonotx with IFN (48wk) - initial response 40%, sustained response
  • Compared to HBVHCV tx No transient acute hepatitis ALT fall precipitously during tx90% virologic response seen in first 12 wksDurable virologic response for 5-6yrs in successful tx, normal ALTand improved histology ----- almost cure

  • Good prognosisLow baseline viral load < 2million c/mlHistologically mild hepatitis, minimal fibrosisFavorable genotype 2, 3 than 1, 4Age 80% adheranceBrief duration of infectionLow HCV quasispecies diversityImmunecompetenceLow liver iron level

  • Interferon CytokineAttach on cell surface receptorSignal Janus activated kinase and signal transducers and activate transcription, induction of genes Double stranded RNases, viral protein inhibitors, destabilisers of viral messanger RNAImmune response genes activation of natural killer cells, maturation of dendritic cells, proliferation of memory T cells, prevention of T cell apoptosisIncreased drug dose and rapid infected hepatocyte death is related to rapid viral clearanceINF 3million IU sc 3X/wk before bed time

  • Adverse effects of TxINFMuscle ache, fatigue, depresion, anxiety, irritability, sleep disturbance, concentration difficultyAutoimmune rxn thyroiditis, alopecia, rashes, diarrhea, numbnessSerious side effects permanent injury and death 1-2% from combinationPt information and monthly check ups sx and cbc30-40% require dose reduction, 20% discontinuation

  • ribavirinOral nucleoside analogueMech against HCV not clearMinimal direct activityLead to rapid and lethal mutation of virionsDepletion of intracellular guanosine triphosphase necessary for viral RNA synthesisHas immune modulatory effects Dose - 1200mg for >75Kg/ - 1000mg for
  • contraindicationsAbsolutePregnancy, lactation, allergy to the drugsRelativeDecompensated cirrhosisBilirubin >1.5mg/dlPT > 15secINR >1.7Albumin
  • Pegylated interferonPolyethylene glycol attachment to INFExtended half life, given once a wkDose depend on wtHigher response rate than the conventional tx with INF + ribavirinPeg INF- 2a and 2b Comparable efficacy, INF 2a well tolerated

  • responsesSustained 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 fibrosisTransient virologic response, relapse 20%, breakthrough 10%Reappearance of HCV RNA, rise in ALT, common with short coarse tx and monotherapyNon responseHCV RNA remain detectable and ALT remain raisedCommon with genotype 1 (30%), rare in genotypes 2, 3.

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

  • Areas of uncertainityTx for childrenTx acute hepatitis C>85% virologic response if tx initiated in 6 months timeOr 75% progress to chronic phaseHigh side effects in acute txImproving side effects and cost (30-40,000USD)Futile to continue tx in genotype 1 if RNA positive at 24wkPrediction If no 2log10IU/ml viral drop or undetectable by 12 wk --- 98-100% non responseRapid 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

  • Liver transplantFor decompensated HCV related cirrhotic pts, and early stage HCCReinfection of graft inevitableAccelerated disease progression (in immuno suppressed) Pre and post transplant viral suppression, New tx neededSimilar 1 and 5 yr survival rate with other liver transplant cases ??

  • Co infection with HIV1Increased risk of disease progressionTx early regardless of ALT, histologyPoor rates of response to monotherapy like HCV infection aloneSimilar efficacy as a lone HCV with combination txHAART immune reconstitution, hepatotoxic drugs exacerbate hepatitisInitiat tx for HCV before HAART

  • Potential target for future drug developmentHCV proteases helicasePolymeraseInternal ribosomal entry sitePutative cell surface receptor CD81Newer INF

  • preventionIneffective Ig, vaccine - - immunoprophylaxis not feasibleChemoprophylasis noneUniversal precautions Screening transfusion blood and blood productsSterile interventional materialsAvoid sharing razor blade, nail clippers.Avoid multiple sexual partnership, use barriersNo fear in stable monogamous sexual partnersNo special precaution for babies from infected mothersNo restriction of breast feeding