Dr. Alipour

 Chronic hepatitis C virus (HCV) infection is one of the most common chronic liver disease and accounts for 8000 to 13,000 deaths each year.  The majority of liver transplants performed in the United States are for chronic HCV.

 The CDC estimates that the number of new cases of acute HCV infection in the United States was 230,000 per year in the 1980s to its current level of about 19,000 cases per year  The overall incidence in 2006 was estimated to be 0.3 per 100,000

 The decline relates primarily to reduced infections in injection drug users  Transfusion-associated hepatitis has had little impact on the recent change in the incidence of HCV infection  Despite the overall decline in HCV, infection rates among young adults may be increasing between 2002 and 2009 among age 15 to 24 years.

 Intravenous drug use  Blood transfusion  Sex with an intravenous drug user  Having been in jail more than three days  Religious scarification  Having been struck or cut with a bloody object  Pierced ears or body parts  Immunoglobulin injection

 Illicit drug use  Blood transfusion  Hospitalization  Organ transplantation  Sexual or household contact  Perinatal transmission  Hemodialysis  Other

 WHO SHOULD BE TESTED(AASLD)  IVDA in the recent and remote past, including those who injected only once  Those with conditions associated with a high prevalence of HCV including: patients with HIV infection hemophilia who received clotting factor concentrates before 1987 hemodialysis pts and those with unexplained abnormal aminotransferase levels

 Prior recipients of transfusions or organ transplants before July 1992  Children born to HCV-infected mothers  Healthcare, emergency and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood  Current sexual partners of HCV-infected persons

 Screening assays designed to detect antibody anti-HCV with high sensitivity(EIA)  Supplemental assays designed to help identify false positive screening test(RIBA and HCV RNA)

 EIA HCV RNA RIBA

 HIV patients  Dialysis patients  Organ transplantation  In those with unexplained liver disease whose anti-HCV test is negative

 HCV RNA assays:  Qualitative TMA method lower limit 10 IU/ml Amplicor method lower limit 50 IU/ml  Quantitative

 Quantitative assays are used before treatment to measure baseline HCV viral load and during treatment to assess on-treatment response.

 Pts with a low pretest probability of infection :  Pts without risk factors for HCV who have a positive EIA-2 (such as blood donors) require confirmatory testing, particularly if they have no biochemical evidence of chronic liver disease (HCV RNA Qualitative or RIBA)

 Pts with a high pretest probability of infection:  Over 90% of pts with biochemical or clinical evidence of chronic liver dis. and a positive EIA-2 particularly if they have risk factors for HCV infection such as a Hx of transfusion, injection drug use, nasal cocaine use, or other percutaneous exposures should undergo quantitative HCV RNA determination

 Spontaneous clearance of virus  Technical reasons  Passively acquired from blood transfusions  Maternal anti-HCV antibodies in babies  Viremia may be intermittent  HCV RNA may be below the limit of detection

 Patients who are HCV RNA negative and EIA positive should be retested in several months since some will be false negatives

 Pts diagnosed with HCV should also be tested for HIV and hepatitis B due to the common modes of transmission  Alcohol abstinence  NSAIDs should be avoided in pts with advanced liver dis.  Acetaminophen not exceed 2 g per 24 hours

 Screening for esophageal varices and HCC in cirrhotic pts  Vaccination including: HAV vaccine HBV vaccine

 Before antiviral therapy is started:  LFT  CBC  TSH level  A pregnancy test is required in women  The HCV genotype and serum HCV RNA level

 HCV genotyping is essential before treatment, since the genotype defines the duration of therapy and dose of ribavirin.  In addition, the genotype is an important predictor of the likelihood of obtaining a SVR.

 A 2009 guideline of AASLD recommends:  liver bx be considered in pts with chronic HCV if the pt and provider wish information regarding fibrosis stage for prognostic purposes or to make a decision regarding Rx.  Establish the presence of concomitant diseases  The guideline also notes that the noninvasive tests are useful for defining the presence or absence of advanced fibrosis

 18 years of age or older  HCV RNA detectable in the serum  Liver bx with chronic hepatitis and significant fibrosis  compensated liver dis  Acceptable hematologic and biochemical indices  Willing to be treated and conform to treatment requirements  No contraindications to treatment

 Total serum bili <1.5 g/dL  INR <1.5  Albumin >3.4 g/dL  Platelet count >75,000 cells/mm3  No evidence of hepatic encephalopathy or ascites  Acceptable hematological and biochemical indices  Hemoglobin >13 g/dL for men and >12 g/dL for women  Neutrophil count >1500 cells/mm3  Creatinine <1.5 mg/dL

 Pts who failed prior treatment  Current users of illicit drugs or alcohol who are willing to participate in a substance abuse program  Liver bx without fibrosis or mild fibrosis  Acute hepatitis C

 Coinfection with HIV  Less than 18 years of age  Chronic kidney disease either requiring or not requiring hemodialysis  Decompensated cirrhosis  Recipient of a liver transplant

 Major, uncontrolled depressive illness  hypersensitivity to drugs  A kidney, heart, or lung transplant  Autoimmune hepatitis  Untreated thyroid disease

 Severe concurrent dis. such as severe HTN, heart failure, significant CAD, poor controlled diabetes, COPD  Less than two years of age  Pregnant, contemplating pregnancy (including men), or unwilling to assure contraception

 Withhold treatment if: HCV acquisition before the age of 35 years Female sex Alcohol abstinence No or minimal fibrosis on liver biopsy  Treat if: Initial biopsies show moderate activity or some degree of fibrosis

 HCV genotype (genotypes 2 and 3 are more responsive to treatment than genotypes 1 and 4)  Baseline viral load (≤600,000 to 800,000 IU/mL)  Race (whites have higher response rates than African Americans and Latino whites)  Host genetic factors (eg, IL28B polymorphisms)  Use of combination therapy with peginterferon and ribavirin  Treatment adherence

 RVR: HCV RNA negativity after 4wks of treatment; if the HCV RNA remains negative at 12 wks it is known as an extended rapid virologic response (eRVR)  EVR: at least a 2 log reduction in HCV RNA (a partial EVR) or HCV RNA negativity (a complete EVR) by wk 12 of treatment  Delayed virologic response: HCV RNA negativity at week 24 in pts who fail to achieve a complete EVR (such patients are also known as "slow responders")  End of treatment response (EOT): HCV RNA negativity at the end of treatment  SVR: absence of HCV RNA by PCR six months after stopping treatment

 peginterferon alfa-2a(Pegasys), the dose is 180 micrograms SQ/wk  peginterferon alfa-2b(Peg-Intron), the dose is 1.5 microgram/kg SQ/wk

 Peginterferon + ribavirin  Ribavirin is not weight-based  All pts receive 800 mg in daily divided doses (typically 400 mg twice daily)  Duration:24 wks  Better response to peg+ ribavirin than genotype 1 or 4

 Ribavirin is weight-based  Peg alfa-2a+ ribavirin 1000 mg if weight=< 75 kg  1200 mg if weight >75 kg  Peg alfa-2b+ ribavirin 800 mg if wt<65 kg  1000 mg if wt 65 to 85 kg  1200 mg if wt >85 to 105 kg  1400 mg if wt>105 kg  Duration: 48wks

 Pts who achieve an SVR who do not have cirrhosis do not require any specific follow- up for their HCV  But some will check an HCV viral load one year after the completion of treatment to confirm that the pt has SVR  Pts who fail to achieve an SVR should be followed for signs of progression of their liver dis.

 Most pts should receive therapy with peginterferon, weight-based ribavirin, and a protease inhibitor( boceprevir or telaprevir).  The addition of a PI to regimens increases SVR rates from 40-50% to 70-80%

 Dual therapy: peg+ ribavirin  Triple therapy: peg+ ribavirin+ PI  Protease inhibitors should never be used as monotherapy due to the development of resistance

 Treatment-naïve: have never received any treatment for HCV  Prior relapsers: Patients who had an undetectable viral load at the end of treatment but who did not achieve a SVR  Partial responders: who achieved a 2 log drop in HCV RNA by week 12 of treatment but who did not achieve an end of treatment response  Null responders: who did not achieve a 2 log drop in HCV RNA by week 12 of treatment

 Telaprevir is only used for the treatment of pts with genotype 1  Telaprevir is given as 750 mg (two 375 mg tab.) 3 times per day with food (not low-fat)

 Boceprevir is given as 800 mg (four 200 mg capsules) 3 times/day starting at week four of treatment  Boceprevir should be given with food.

 The most frequent side effects of interferon:  Flulike symptoms (in>90% of pts)  Alopecia (in 10% to 30%)  Depression  Hypothyroidism  Hyperthyroidism

 Anemia  Cough  Pharyngitis  Insomnia,  dyspnea, pruritus, rash, nausea, and anorexia are the most common side effects  The most serious side effects are anemia and teratogenic effects.

 Hemolytic anemia is reversible and usually resolves within the first month after therapy is stopped  If anemia is severe or slow to recover, the pt's iron stores should be assessed  Administration of hematopoietic growth factors (e.g,erythropoietin) may enable a pt to continue full-dose peginterferon+ribavirin.

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