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Viral hepatitis c. corrected

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  • 1. Dr. Afzal Haq Asif Associate Professor Pharmacology & Therapeutics Nov Dr. Afzal Haq Asif
  • 2. Clinical Case  A 45-year-old woman with a history of blood transfusion is seen in the clinic for complaints of tiredness, fatigue, anorexia, and weakness.  On Physical examination, nothing was remarkable  Laboratory values reported today include AST 150 IU/mL, ALT 250 IU/mL , SCr 0.9 mg/dL,  Bilirubin: 2.0 mg/dL, albumin 2.5 g/dL.  Serum Anti HCV : + HCV RNA level: 1, 220200 IU/mL  A liver biopsy has revealed severe necro-inflammation and bridging fibrosis.  What is diagnosis ?  What is the best course of action? Nov Dr. Afzal Haq Asif
  • 3. ILO’s  At the end of the session, the attendee will be able to  Define the acute and chronic viral hepatitis C  Diagnose based upon clinical and lab data  Design therapeutic objectives  Design therapeutic and follow up evaluation plan for patient  Resolve drug related problems of patient  Educate the patient to improve therapeutic outcome Nov Dr. Afzal Haq Asif
  • 4. Introduction  In 60’s only A & B  In 70’s, it was found that neither agent is found responsible for post trans fusion Hepatitis, So Hepatitis caused by NANB was introduce  The major cause of parenterally transmitted NANB hepatitis. In 1989, the genome was cloned from the serum of an infected chimpanzee. Nov Dr. Afzal Haq Asif
  • 5. Introduction: fact sheet  An estimated 130–170 million people are infected with      Nov hepatitis C worldwide Out of 100 people who contract the infection, 75–85% will develop chronic infection, 60–70% develop chronic liver disease, 5–20% develop cirrhosis over the course of their chronic infection, 1–5% will die of complications including hepatocellular carcinoma (HCC) 7.3 % individuals were found seropositive for Anti-HCV antibodies in a study carried out on 15323 Saudi patients Dr. Afzal Haq Asif
  • 6. Figure 1. Seroprevalence of anti-HCV antibodies using chemiluminescent microparticle immunoassay. The total seroprevalence among the 15323 tested individuals. B. HCV seroprevalence in males in comparison to females Abdel-Moneim AS, Bamaga MS, Shehab GMG, Abu-Elsaad A-ASA, et al. (2012) HCV Infection among Saudi Population: High Prevalence of Genotype 4 and Increased Viral Clearance Rate. PLoS ONE 7(1): e29781. doi:10.1371/journal.pone.0029781 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029781 Nov Dr. Afzal Haq Asif
  • 7. HCV  HCV is a single stranded RNA virus  Genus Hepa-civirus, (HCV)  Family Flavi-viridae  Characterized by a high spontaneous mutation rate  11 genotypes (90 sub-types) , (1a, 1,b, 2a, 3b etc)  USA:   Genotype 1 (subtypes 1a, 1b, and 1c) 70%–75%. Genotypes 2 (subtypes 2a, 2b, and 2c) and 3 (3a and 3b) are less common  KSA:    Nov Genotype helps determine therapy duration and likelihood of responding to therapy Genotype 4 is common Ia And Ib less common Genotype 2, 3, 5 and 6 are least common Dr. Afzal Haq Asif
  • 8. Epidemiology  Worldwide seroprevalence 3% based upon anti- HCV) up to 180        Nov million people infected chronically. Variation in distribution 0.4% to 1.1% in North America to 9.6% to 13.6% in North Africa. A primary cause of death from liver disease The leading indication for liver transplantation in the United States Deaths as a result of liver failure or HCC) will continue to rise in the next two decades Responsible for 85% of cases associated with posttransfusional NANB hepatitis Occurs among persons of all ages, highest between 20 to 39 years, with a male predominance. Blacks have a substantially higher prevalence of chronic HCV infection than do whites. Dr. Afzal Haq Asif
  • 9. Transmission  Mainly blood-borne (transfusion, intravenous drug abuse)  High risk: Transfusion, intravenous drug abuse  Low risk:  Snorting cocaine or other drugs  Occupational exposure needle stick , health workers  Body piercing and acupuncture with unsterilized needle  Tattooing  From pregnant mother to child  Nonsexual household contacts (rare)  Sharing razors and/or toothbrushes Nov  Sexual transmission Dr. Afzal Haq Asif
  • 10. Pathogenesis: replication in Liver cells Nov Dr. Afzal Haq Asif
  • 11. Pathogenesis  Direct cell injury due to viral replication  Genotype 1 is associated with higher viral replication, and infection with the type 1b genotype is associated with more progressive liver disease  Immune mediated cell injury:  CD8+ and CD4+ lymphocytes in portal, peri-portal, and lobular areas in patients with HCV infection Nov Dr. Afzal Haq Asif
  • 12. Course of disease  Associated with Acute and Chronic Infections Nov Dr. Afzal Haq Asif
  • 13. Course of the Disease  Asymptomatic: 30%  Moderate to severe hepatitis in 30% <20 years of age  70-80% develop chronic infection  Presence of viral RNA in serum for 6 months or more  Evidence of viral replication: viral load  10-30% of develop cirrhosis  Nov Factors promoting cirrhosis:  Alcohol use,  Male sex,  Age over 40 years at the time of infection  Co-infection with HIV and/or HBV  The 5-year mortality with compensated cirrhosis 9%,  Decompensated cirrhosis had a 5-year mortality of 50% Dr. Afzal Haq Asif
  • 14. Course of the Disease, contd;  Hepatocellular Carcinoma in HCV infection  1% to 4% of patients per year during the first 5 years after cirrhosis develop hepatocellular carcinoma  7% after 5 years of cirrhosis  14% at 10 years;  Higher in men  Higher in older patients NIH Consensus Program. National Institutes of Health consensus development conference panel statement: management of hepatitis C. Hepatology. 1997;26:2S-10S. Nov Dr. Afzal Haq Asif
  • 15. Extra-hepatic manifestations  Rheumatoid arthritis  Glomerulonephritis  Cryo-globenemia Nov Dr. Afzal Haq Asif
  • 16. Spontaneous resolution  Early studies  15–25% of persons who developed transfusion- associated acute hepatitis C,  14–29% HCV-infected blood donors, persons with ‘community-acquired’ infection, IV drug abusers and children with leukemia  Later studies:  42 and 45%. among infected children (21, 29), young women (20, 22) and even some persons with community-acquired hepatitis C  Young age at the time of infection is an important determinant of the likelihood of spontaneous recovery. The historyof the‘‘natural history’’of hepatitisC(1968-2009): Liver International 2009; 29(s1): 89–99 Nov Dr. Afzal Haq Asif
  • 17. Diagnosis  Clinical Signs and symptoms: not suggestive, unless thorough history and Labs  Serum anti-HCV antibodies: 99% sensitivity and specificity  Serum HCV RNA: “Viral Load”  Quantitative: used for   Confirmation of Diagnosis Monitoring response to therapy  Qualitative:   50 IU/ml: 100 copies/mL to confirm diagnosis 98% specificity AASLD does not recommend qualitative  Liver biopsy: for cirrhosis, prognosis  ALT: Non specific  Genotype: forDr. Afzal Haq Asif duration and response treatment Nov
  • 18. AASLD, (American Association for the Study of Liver Diseases) guidelines-2009 Nov Dr. Afzal Haq Asif
  • 19. Who should be screened  Persons who have injected illicit drugs in the recent and remote past  Persons with conditions of a high prevalence of HCV infection including:  With HIV infection  With hemophilia who received clotting factor prior to 1987  Who have ever been on hemodialysis  With unexplained abnormal aminotransferase levels  Immigrants from countries with a high prevalence of HCV infection  Prior recipients of transfusions or organ transplants prior to July 1992:  Persons who were notified that they had received blood from a donor who later tested positive for HCV infection  Persons who received a transfusion of blood or blood products  Persons who received an organ transplant  Children born to HCV-infected mothers  Health care, emergency medical and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood  Current sexual partners of HCV-infected persons Nov Dr. Afzal Haq Asif
  • 20. Prevention  No Vaccine is available  Risk factor modification  Intravenous drug abuse: treatment with oral methadone  Sexual contact: appropriate barrier contraception  Avoid blood exposure: Occupational (universal precautions) or other contact  Avoid sharing toothbrushes or razors or receiving a tattoo  HAV and HBV vaccine to prevent further progression of liver disease Nov Dr. Afzal Haq Asif
  • 21. Nov Dr. Afzal Haq Asif
  • 22. Goals of Therapy  Eradicate HCV infection in acute  Decrease HCV associated morbidity and mortality  Attain Sustained Virologic Response (SVR)  Undetectable HVC RNA, 24 weeks after therapy completion These goals  Normalize biochemical markers  Improve clinical symptoms are partly achieved by Pharmacotherapy  Prevent progression to cirrhosis an HCC  Prevent development of end stage liver disease  To prevents the development of chronic HCV infection Nov Dr. Afzal Haq Asif
  • 23. Acute HCV infection  PEG- INF α based therapy for 12-24 weeks  Ribavirin may be added: but no study is available to favor improve SVR  Treatment can be delayed for 8-12 weeks for to assess for spontaneous resolution  Meta-analysis of 16 trials resulted in a risk difference of 49% (95% CI 33-65), for developing chronic infection between treated and untreated patients Nov Dr. Afzal Haq Asif
  • 24. Treatment of Chronic HCV infection  Indications of therapy:  Age older than 18 years and positive serum HCV RNA  On biopsy moderate to severe inflammation/necrosis  Compensated liver disease, acceptable hemoglobin (13 g/dL men, 12 g/dL women) and neutrophils (more than 1500/mm3), SCr less than 1.5 mg/dL  Willingness to be treated and be adherent  No contraindications to therapy Nov Dr. Afzal Haq Asif
  • 25. Treatment of Chronic HCV infection  Contraindications to treatment  Major uncontrolled depressive disorder  Solid-organ transplantation (renal, heart, lung)  Autoimmune hepatitis or other autoimmune conditions  Untreated thyroid disease  Pregnant or unwilling to adhere to adequate contraception  Severe concurrent medical disease (hypertension, heart failure, coronary heart disease, poorly controlled diabetes mellitus, chronic obstructive pulmonary disease)  Age younger than 2 years  Hypersensitivity to IFN or ribavirin Nov Dr. Afzal Haq Asif
  • 26. Treatment of Chronic HCV infection  Difficult patient population: individualized consideration  Normal ALT (treatment dependent on genotype, degree of        Nov fibrosis, symptoms) Liver biopsy indicating no or mild fibrosis Advanced liver disease (fibrosis or decompensated cirrhosis) Recurrence after liver transplantation Patients younger than 18 years Co-infection with HIV or HBV Chronic Kidney Disease Non responders or relapses Dr. Afzal Haq Asif
  • 27. Treatment  First-line treatment for acute HCV includes pegylated interferon plus ribavirin.  once-weekly PEG-IFN and a daily oral dose of ribavirin in two divided doses Genotype 1 2,3 Pegylated-IFN Dose Peginterferon α2a 180 mcg/wk Peginterferon α2b 1.5 mcg/wk Peginterferon á2a 180 mcg/wk Peginterferon α2b 1.5 mcg/wk weight Ribavirin Dose Duration Less than 75 Kg 1000 mg 48 weeks More than 75 kg 1200 mg 800 mg At week 1, 2, 4 and then interval of 4-8 weeks monitor: • Symptom of Disease • Side Effects of therapy • Blood count • Aminotransferases Nov Dr. Afzal Haq Asif 24 weeks
  • 28. Treatment: Genotype 4  A meta-analysis leads to recommendations for patients with genotype 4:  Combination therapy with Peg IFN plus ribavirin for 48 weeks.  Combination of Peg IFN-α2b plus a fixed dose of ribavirin (10.6mg/kg/day) for 36weeks may also result in a sufficient EVR.  genotype 6:  with Peg IFN-α plus ribavirin for 48 weeks was more effective than treatment for 24 weeks. Nov Dr. Afzal Haq Asif
  • 29. Follow up  Genotype-1  AT week 12  Retest HCV RNA level  If Negative or decreased by 2log 10 units  Continue for full 48 weeks  Monitor for : Symptoms  Blood count  ALT at 4-8 week interval   If RNA hasn’t fallen by 2log 10 Units: STOP therapy  Genotype 2, 3  Retest HCV RNA level at 24 weeks:  After therapy:  Assess ALT 2, & 6 months  Repeat HCV RNA, 6 months after stopping tx Nov Dr. Afzal Haq Asif
  • 30. Ribavirin adverse effect monitoring  Oral nucleoside analog  Available as 200-mg tablets (Copegus) or capsules (Rebetol)  Adverse Effect  Hemolytic anemia: Upto 10% of patients (usually within 1–2 weeks of initiating therapy):  decrease dose to 600 mg/day when hemoglobin drops to 10 g/dL or less, and discontinue when hemoglobin drops to 8.5 g/dL or less May worsen underlying cardiac disease; Monitor complete blood cell count (CBC) at baseline, 2 weeks, 4 weeks, Decrease dose to 600 mg/day if hemoglobin drops more than 2 g/dL in any 4-week period during treatment. May use epoetin or darbepoetin to stimulate red blood cell production, improve anemia      Nov (J Dr. AfzalGastroenterol 2005;39:S9-S13), Clin Haq Asif
  • 31. Ribavirin adverse effect monitoring  Teratogenicity: Category X drug;  Requires a negative pregnancy test at baseline and every month up to 6 months after treatment,  Use of two forms of barrier contraception during treatment and for 6 months after treatment.  Contraindicated in patients with a creatinine clearance (CrCl) less than 50 mL/minute  pancreatitis, pulmonary dysfunction (dyspnea, pulmonary infiltrate, and pneumonitis), insomnia, irritability or depression (often referred to as “riba rage”), and pruritus. Nov Dr. Afzal Haq Asif
  • 32. Interferon  INF α 2 b:  Used for HBV and HBC infections  Half life : 2-3 hours  Dose: 3 MIU subcutaneous 3 times /week   Geno-1: 4/48 weeks Geno2: 3/24 weeks  Peg IFN α2 a: with branched peg  Used for HBV and HVC infections  Half life: 160 hours  Dose: 180 mcg s/c once weekly  Nov chain  Half life: 40 hours  Dose 1.5 mcg/kg s/c once weekly  IFN alfaxon-1:  Used for HCV treatment  Dose: chain   PegIFN -α2b : linear peg Geno-1 4/48 Geno-2 3/24     Dr. Afzal Haq Asif naïve: 9 mcg Non responder: 15 mcg s/c 3 times a week Naïve for 24 weeks INF non responder: 48 weeks
  • 33. Interferon: adverse effects  Most Common:  influenza-like symptoms (e.g., fever, headache, myalgia, fatigue),  Hematologic abnormalities: neutropenia, thrombocytopenia,  Neuropsychiatric disorders (e.g., depression 40 % and anxiety),  injection site reactions,  diarrhea, nausea, insomnia, alopecia, pruritis, and anorexia.  Less common but serious adverse  severe psychiatric (i.e., suicidal ideation),  cardiovascular (i.e., myocardial infarction),  Endocrine (e.g., thyroid dysfunction, diabetes mellitus),  immune (e.g., psoriasis, lupus),  pulmonary, and ophthalmologic disorders,  pancreatitis, colitis, and other serious infections. Nov Dr. Afzal Haq Asif
  • 34. Managing the adverse effects of interferon  Hematological:  Anemia: common reason for discontinuation and dose reduction (upto 23% of patients)  Tx: Erythropoitic growth factor:  Epoitin Alfa: 40-6000 units weekly  Darbepoitin alfa 3 mcg every 2 weeks  IFN induced neutropenia:  Recombinant granulocyte colony stimulating factor (filgrastim) is safe and effective  Thrombocytopenia:  Nov Eltrombopag, an orally active thrombopoietin receptor agonist that received FDA approval for chronic ITP (hepatotoxic) Dr. Afzal Haq Asif
  • 35. Managing the adverse effects of interferon  Neuropsychiatric:  Prompt recognition and early treatment required  Depression: 44% during first 3 months  Tx:    Nov Close monitoring and follow up by a team of health care providers including psychiatrist Prophylactic anti-depressants are debated Uncontrolled psychiatric symptoms: contraindication for Tx Dr. Afzal Haq Asif
  • 36. Treatment Challenges  High viral load  HCV RNA greater than 800,000 IU/mL  Advanced fibrosis and cirrhosis,  Continued drug and/or alcohol use,  Psychiatric conditions,  Coinfection with HBV or HIV, advanced age,  Immunosuppression (e.g., liver transplantation recipients),  African American race,  Obesity and insulin resistance,  Previous treatment with suboptimal therapy Nov Dr. Afzal Haq Asif
  • 37. African Americans: variable response  Result of 2 prospective , multicenter clinical trials,  In African American patients, SVR occurred in only 19% to 28% of HCV genotype 1 infected African American patients treated with pegIFN and ribavirin therapy, in contrast to the 40% to 50% seen in other studies  Difference cannot be explained  New strategies: ??? Nov Dr. Afzal Haq Asif
  • 38. HIV and HCV co-infection  30% HIV patient also have HCV infection  Rapid progression of liver damage  SVR is lower as compared to HVC alone  A threshold CD4 count of at least 350 cells/μL has been suggested for initiation of antiviral therapy;  Treatment is not recommended if CD4 counts lower than 200 cells/mL.  Adverse effects are more common:  Anemia with Ziduvodine and Ribavirin combination  Mitochondrial toxicity, pancreatitis, liver failure, and death ; more common with Didanosine and Ribavirin combination  ???? Liver transplant Nov Dr. Afzal Haq Asif
  • 39. Treatment Nonresponsive or relaps  No specific treatment regimen for chronic HCV infections not responding to, or relapse after, pegIFNbased therapy.  High-dose IFN alfacon-1 in combination with ribavirin is currently being evaluated in clinical trials for partial or no response to pegIFN-based therapy  Extension to 72 weeks: needs evidence Nov Dr. Afzal Haq Asif
  • 40. Liver Transplant. Is this a solution?  Most common indication in US:  Hepatitis C virus–related end-stage liver disease  Outcome:  Recurrence is essential outcome  Progression of liver disease is accelerated, Within 5 years after transplantation, 20% to 40% of liver allografts progress to cirrhosis;  60% to 70% of cirrhotics experience hepatic decompensation within 3 years  Response rates to pegIFN and ribavirin treatment after liver transplant are lower than for patients in the pretransplant setting,  Drug toxicity remains a limiting factor. 1/3 require discontinuation Nov Dr. Afzal Haq Asif
  • 41. Dealing with the challenges: New antivirals  Direct Acting Antiviral Drugs (DAA)  The NS3 protease inhibitors   Nov Telaprevir and Boceprevir An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practiceguideline by the American Association for the Study of Liver Diseases Dr. Afzal Haq Asif
  • 42. Treatment updates Add on therapy for Genotype-1:  Boceprevir: Protease inhibitor : (DAA)  Indicated for:      Adult naïve patients Who failed previous treatment with Peginferon + ribavirin SVR rate with triple therapy is 63-66% in comparison to double therapy (50%) Higher incidence of anemia and neutropenia Monitor after every 4 weeks  Dose:   800 mg t.i.d. with food (200mg cap available) with double therapy Added to double therapy at week 5  If RNA viral load is > 100 IU/ml at week 12  Decreased at week 12 but Detectable at week 24 Nov Dr. Afzal Haq Asif Stop Therapy
  • 43. Treatment updates Add on therapy for Genotype-1  Telaprevir: protease inhibitor  Indicated for:     Adult naïve patients Who failed previous treatment with Peginferon + ribavirin SVR rate with triple therapy 72-79% in comparison to double therapy (50%) Anemia, skin rash, pruritus, nausea, diarrhea, ano-rectal discomfort  Dose:   Nov 750 mg t.i.d after 30 minutes of food (with 20 g of fat) for absorption If Start with double therapy from day 1 continue upto 12 weeks Dr. Afzal Haq Asif
  • 44. Nov Dr. Afzal Haq Asif
  • 45. Outcome evaluation parameters Parameter Rapid virologic response (RVR) Early virologic response (EVR) Definition Undetectable HCV RNA at week 4 of treatment End-of-treatment response (ETR) Sustained virologic response (SVR) Breakthrough Undetectable HCV RNA at the end of a 24- or 48-week course depending on genotype Undetectable HCV RNA 24 weeks after finishing treatment Reappearance of HCV RNA while on treatment Relapse Reappearance of HCV RNA after finishing a course of treatment Failure to clear HCV RNA from serum after 24 weeks of therapy Failure to decrease HCV RNA by < 2 logs after 24 weeks of therapy Decrease in HCV RNA Nonresponder Null responder Partial responder Nov > 2-log reduction in HCV RNA compared with baseline or undetectable HCV RNA at 12 weeks Dr. Afzal Haq Asif
  • 46. Outcome evaluation  Disease:  As discussed above + Check ALT after every 4 weeks  Therapy  Patient on Peginterferone: and Ribavirin or Peginterferone alone:  Check WBC, ANC (absolute neutrophil count ), platelets and Hemoglobin  weekly or biweekly during first month  Monthly after first month  Monitor TSH and fasting lipid panel every 12 weeks  Monitor serum creatinine in patients receiving ribavirin  Nov To avoid ribavirin accumulation in renal insufficiency resulting in Hemolytic anemia Dr. Afzal Haq Asif
  • 47. Patient care and education-1  Educate patient for risk factors for acquiring hepatitis  Educate patient about hepatotoxic drugs  Educate regarding vaccination against A & B  Obtain thorough PMH regarding psychiatric, cardiac,     Nov endocrine and renal disorders Assess fro adverse effects periodically Encourage for medication compliance to increase SVR Encourage fluid intake to avoid dehydration Educate all women of child bearing age, and men who are able to father a child to use 2 forms of contraception during and 6 months after therapy Dr. Afzal Haq Asif
  • 48. Patient care and education contd-2  Provide patient education:  How to prevent viral hepatitis  Importance of taking all medication daily at scheduled time  Adverse effects of medications  How to self administer pegylated interferon injection correctly  Importance of appropriate disposal of used injection Nov Dr. Afzal Haq Asif
  • 49. References  Houghton M Discovery of the hepatitis C virus.Liver Int. 2009     Nov Jan;29 Suppl 1:82-8. doi: 10.1111/j.1478-231.2008.01925.x. World Health Organization HepatitisC Fact Sheet 2012. http:// www.who.int/ mediacentre/factsheets/ fs164/en/). [Accessed 26 January 2013]. Wise M, Balek S, Fineli L, et al. Changing trends in hepatitis C-related mortality in the United States, 1995–2004. Hepatology 2008; 47:1128– 1135. ACCP updates on therapeutics-2011 http://www.annualreviews.org/doi/pdf/10.1146/annurev-pharmtox011112-140254 Dr. Afzal Haq Asif
  • 50. Thank You Very Much Nov Dr. Afzal Haq Asif