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HEPATITIS C VIRUS INFECTION

HEPATITIS C VIRUS INFECTION. VALERIE FLETCHER, M.D. INFECTIOUS DISEASES SOUTHERN OHIO MEDICAL CENTER. INTRODUCTION. Hepatitis C virus (HCV) is the most common chronic blood-borne viral infection in North America. Major cause of chronic hepatitis.

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HEPATITIS C VIRUS INFECTION

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  1. HEPATITIS C VIRUS INFECTION VALERIE FLETCHER, M.D. INFECTIOUS DISEASES SOUTHERN OHIO MEDICAL CENTER

  2. INTRODUCTION • Hepatitis C virus (HCV) is the most common chronic blood-borne viral infection in North America. • Major cause of chronic hepatitis. • Causes progressive hepatic fibrosis which leads to cirrhosis and an increased risk of hepatocellular carcinoma. • HCV liver disease is the most common reason for liver transplantation in USA.

  3. THE VIRUS • HCV is an RNA virus and a member of the Flaviviridae family, genus Hepacivirus. • There are 6 known genotypes and more than 50 subtypes (quasispecies). • Type 1 (75%), type 2 (10%) and type 3 (10%) are the commonest genotypes in USA. • There is a lack of a robust T-lymphocyte response to, and a high rate of mutations within the genotypes, thus allowing HCV to elude the immune system-mediated clearance and so produce chronic infection.

  4. EPIDEMIOLOGY • Estimated 4 million people in USA infected with HCV; 2.7 million have chronic infection. • 35,000 new cases per year. • 8000 – 10,000 deaths per year from HCV-related chronic liver disease. • Estimated prevalence is 1.8% of population. • Many persons with chronic HCV have yet to be diagnosed. • A fourfold increase in the number of persons diagnosed with chronic HCV is projected from 1990 -2015. Management of Hepatitis C: 2002. NIH Consensus Development Conference Statement

  5. Persons aged 40 – 59 years have the highest seroprevalence. • High HCV seroprevalence rates (15 -50%) in specific populations (homeless, incarcerated, injection drug users and persons with hemophilia treated with clotting factors before 1992). • 70 to 90% seroprevalence in IDU. • Source of infection unknown in many.

  6. TRANSMISSION • Blood transfusion before 1992. • Injection drug use. • Solid organ transplantation from infected donor. • Unsafe medical practices. • Occupational exposure to infected blood. • Infected mother to child during birth. • High risk sexual practices. • Intranasal cocaine use. • Body piercing.

  7. IDU and HCV transmission • HCV transmitted efficiently by contaminated needles, syringes and other drug paraphernalia. • Infection is rapidly acquired after initiation of use; > 50% after 5 years. • More easily transmitted than HIV.

  8. Perinatal Transmission • Transmission only from women with positive HCV-RNA at delivery. • Average rate of transmission is 6%, higher if HIV co-infection. • No association with method of delivery and breastfeeding. • Maternal HCV antibodies persist in uninfected infants for approximately 12 months. • Infected infants have a good prognosis.

  9. Transmission between sex partners • Sexual transmission occurs but is inefficient. • Male to female transmission more efficient. • Transmission rare between long term steady partners. • Factors that facilitate transmission between partners unknown.

  10. NATURAL HISTORY • Incubation period is up to ~ 8 weeks. • Acute infection. • > 80% persistent infection. • Slower progression if young age at time of infection and female gender. • More rapid progression if HIV or HBV co-infection, alcohol use

  11. Natural History of HCV

  12. Course of acute HCV in HCW after needle stick injury

  13. CLINICAL FEATURES • The majority of infections are asypmtomatic. • Prodrome of anorexia, nausea vomiting, myalgia and malaise. Diarrhea or constipation, low grade fever and abdominal pain may occur (tender hepatomegaly). • Icteric phase – jaundice may occur after 5 – 10 days. • Convalescent phase. • Acute illness may be mild and subsides in 2 – 3 weeks. Fulminant infection is rare.

  14. LAB • In acute infection, mild leukopenia, hyperbilirubinemia and elevated transaminases may occur. • HCV RNA detected in blood within 1 – 3 weeks of exposure. • HCV antibodies present in 50 – 70% of patients at onset of symptoms, and 90% at 3 months. • Alanine aminotransferase (ALT) levels decline with resolution of symptoms, however, may fluctuate throughout the course of infection. ALT persistently normal in up to 40% person with chronic hepatitis.

  15. Alanine Aminotransferase • Serum ALT testing is inexpensive and noninvasive. • Insensitive means of monitoring disease activity. • A single determination gives limited information, and serial measurements recommended. • Weak association between the degree of ALT elevation and severity of histopathological findings on liver biopsy. • Resolution of ALT elevation with antiviral therapy appears to indicate disease response.

  16. Chronic infection and risk of progression • Chronic inflammation of the liver with persistence of HCV RNA > 6 months. • Sequelae include progressive liver fibrosis, cirrhosis, end-stage liver disease and hepatocellular carcinoma. • Little evidence that viral factors (viral load, genotype) affect the risk of progressive liver disease. • Risk of progression increased by older age at time of infection, male gender, immunosuppression, HBV, alcohol.

  17. As little as 30 g/day in men (2 beers, 2 glasses of wine, or 2 mixed drinks) and 20 g/day in women have a detrimental effect on disease progression. • Other factors include iron overload, nonalcoholic fatty liver disease, hepatotoxic medication and environmental contaminants may also increase progression.

  18. Extra-hepatic manifestations of chronic HCV • ‘Rheumatoid’ symptoms • Keratoconjunctivitis sicca • Lichen planus • Glomerulonephritis • Lymphoma • Essential mixed cryoglobulinemia • Porphyria cutanea tarda • Psychological disorders • Leukocytoclastic vasculitis

  19. LABORATORY DIAGNOSIS • Serologic tests to detect HCV antibodies: - enzyme immunoassay (EIA). False negative in pts on HD, immunodeficiency; false positive in autoimmune disorder. - recombinant immunoblot assay (RIBA) • Target amplification technique to detect HCV RNA (molecular assay) - polymerase chain reaction (PCR). A positive test confirms HCV infection.

  20. HCV TESTING EIA Positive Negative Measure HCV RNA by PCR Negative Positive Low risk High risk RIBA Consider treatment for HCV infection Negative Positive No further workup Previous infection and clearance

  21. LIVER BIOPSY • Provides useful information about the degree of fibrosis in HCV infected patients. This information is important in management decisions. • Is not used for diagnosis of HCV infection. • Used for assessment of severity of inflammation, presence of fibrosis, evaluate possible concomitant disease processes, assess therapeutic intervention.

  22. Liver Histology • Activity (necro-inflammation) – severity and progress. May fluctuate with disease activity or therapeutic intervention. • Fibrosis implies possible progression to cirrhosis. In mild cases, is limited to portal and periportal area. More advanced changes defined by ‘bridging fibrosis’. • Cirrhosis

  23. Fibrosis Scoring Methods

  24. The problems associated with liver biopsy • Cost • Complications –pain, major bleeding, pneumothorax, inadvertent biopsy of kidney or colon, perforation of gall bladder. • Patient aversion • Physician aversion • Specimen size – degree of fibrosis more accurately determined in larger specimens • Lack of specific findings.

  25. MANAGEMENT – Baseline evaluation • CBC • ALT • TSH • ANA • HCV genotype • HCV quantitative viral load • Liver biopsy (recommended) • AFP (if cirrhosis present) • Pregnancy test

  26. MANAGEMENT • Previously untreated patients with detectable HCV RNA, persistently elevated ALT and liver biopsy specimen showing fibrosis (or at least moderate necrosis and inflammation) are at high risk of disease progression and are candidates for therapy. • Pegylated interferon (PEG-INF) combined with ribavirn is currently the best therapy. • Treatment associated with significant side effects. • Several predictors of treatment response have been identified, eg HCV genotype. • An absence of serum HCV RNA 6 months after therapy has been discontinued predicts sustained viral eradication.

  27. MANAGEMENT • PEG-INF 180µg sc weekly and ribavirin 800 – 1200mg po daily x 24 -48 weeks. • Genotypes 2 and 3 associated with better response, and treated for 24 weeks. SVR ~ 76% • Genotypes 1, 4, 5. 6 are less responsive to therapy; if there is early virological response after 12 weeks, therapy is continued for a total of 48 weeks. SVR ~ 50% • Independent predictors of favorable response are non-1 genotype, lower levels of HCV RNA and lower BMI. Other factor are age, race, gender, and presence of cirrhosis.

  28. Side effects of Pegylated interferon • Flu-like syndrome – fever, headache, chills, myalgia, fatigue • Gastrointestinal – nausea, anorexia, diarrhea • Neuropsychiatric – depression, irritability • Skin – alopecia, pruritus, rash, dry skin • Bone marrow – anemia, neutropenia • Cardiovascular – arrhythmia, cardiomyopathy, CHF, angina • Endocrine – hypothyroidism, hyperthyroidism, gynecomastia, DM exacerbation • Liver – liver failure, jaundice • Musculoskeletal – arthritis, muscle weakness and cramps • Reproductive – amenorrhea, impotence, uterine bleeding • Other – respiratory, urinary, vision, hearing disturbances, injection site reaction

  29. Side effects of Ribavirin • Neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia • Teratogenic, embryocidal • Depression, suicidal ideation • Pulmonary toxicity • Nausea, vomiting, colitis, pancreatitis • Hypothyroidism, hyperthyroidism • Myocardial infraction, arrhythmia • Hypersensitivity reaction, rash

  30. Contraindication to combination therapy • Hypersensitivity to drugs • Pregnant women • Men whose partners are pregnant • Hepatic decompensation • Neonates and children • Autoimmune hepatitis • Hemoglobinopathies

  31. Barriers to treatment • Neuropsychiatric illness • Alcohol use • Active illicit drug use • Cost • Poor adherence to therapy • Adverse effects

  32. HCV AND HIV COINFECTION • All patients with HIV should be screened for HCV. • Treatment of co-infected persons individualized. • The course of HCV may be accelerated in HIV co-infection. • HCV co-infection may be associated more rapid progression of HIV. • PEG-INF may cause a fall in CD4 cell count.

  33. End of treatment responses and sustained virologic responses (SVR) in HCV/HIV coinfection treated with INF/PEG-INF and ribavirin (APRICOT)

  34. HIV+ patients on HAART have decreased liver related mortality. • Combination therapy is poorly tolerated. • Lower SVR. • Drug interactions. • Protease inhibitors may be associated with hepatotoxity; NRTI associated with pancreatitis, lactic acidosis and mitochondrial toxicity. • Clinician comfort level low.

  35. Adjunctive therapy • Hepatitis B vaccine series - if non-immune • Hepatitis A vaccine series • Contraception during therapy and for 6 months afterwards • Counseling - avoidance of alcohol and drug, use of condoms to prevent transmission and other STDs. • Support groups

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