transcript
- Slide 1
- Hepatitis C virus Treatment Ermias D (MD)
- Slide 2
- 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
- Slide 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
- Slide 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
- Slide 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
- Slide 6
- 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
- Slide 9
- 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
- Slide 10
- Slide 11
- 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
- Slide 12
- 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.
- Slide 22
- 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
- Slide 23
- 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
- Slide 24
- 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 ??
- Slide 25
- 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
- Slide 26
- Potential target for future drug development HCV proteases
helicase Polymerase Internal ribosomal entry site Putative cell
surface receptor CD81 Newer INF
- Slide 27
- Slide 28
- Slide 29
- 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
- Slide 30