A. Epidemiology

1. Major cause of chronic hepatitis in developed countries
2. Worldwide Prevalence ~170 million
   1. Overall, ~35,000 new cases per year in USA
   2. Prevalence in USA ~1.6% , equating to ~4.1 million infected in USA [3]
   3. Peak prevalence of anti-HCV Abs was 4.3% found in persons age 40-49 years [3,12]
   4. Overall, 5-10% of HCV carriers are coinfected with HIV
   5. About 280,000 deaths per year worldwide attributed to HCV
   6. HCV+ patients are at higher risk for drug abuse-related than liver-reated deaths [11,12]
3. Infection and Chronic HCV [11,12]
   1. Of persons that are anti-HCV antibody positive (Ab+)
   2. About 80% of persons exposed to HCV will develop chronic HCV infection
   3. Chronic HCV infection verified by presence of HCV RNA
   4. Thus, of all HCV Ab+ persons, ~10-20% are HCV RNA negative
   5. ~40% of all chronic asymptomatic HCV is histologically active and progressive [4]
   6. Treatment of acute HCV infection (within months) can lead to complete eradication [5]
4. Transmission
   1. Before detection assays, most commonly associated with blood transfusions
   2. Highest risks now with intravenous drug abuse (IVDA), intranasal cocaine
   3. Overall 65% of cases associated with IVDA
   4. Low risk of sexual transmission in family situations and for blood donors
   5. Sexual transmission in monogamous couples very low
   6. Majority of blood donors with positive HCV antibody have subclinical disease
   7. Blood donors with positive anti-HCV antibody, normal ALT levels, and no HCV RNA by polymerase chain reaction (PCR) have cleared infection
5. Coinfection with HIV [6]
   1. Increases risk of viral persistence after infection
   2. Increases levels of chronic viremia
   3. Overall risk of cirrhosis is very high at ~25% at 15 years
   4. In USA, 150,000-300,000 persons are coinfected with both HIV-1 and HCV
   5. Antiretroviral therapy reduces liver-related mortality in HIV/HCV coinfection [7]
6. Major Complications of Chronic HCV [11,12]
   1. About 30% of chronic HCV develop cirrhosis over 20 years
   2. Alcohol abuse increases risk of cirrhosis ~8 fold in HCV infected patients [8]
   3. HCV is the primary indication for liver transplant in USA (~40% of all transplants)
   4. Hepatocellular carcinoma (HCC) is the most devastating complication of HCV
   5. HCC develops in 1-4% of HCV+ cirrhotics per year
   6. Greatest risk to HCV+ patients is drug abuse
   7. Coinfection with hepatitis B virus (HBV) increases risk of liver-related death, HCC, cirrhosis
   8. Interferon alpha (IFNa) therapy for cirrhotic HCV associated with reduced risk for developing HCC and improved survival [9]
7. Routine general screening for HCV is not recommended [23]

B. Viral Characteristics

1. Single stranded, Genus Flavivirus (RNA virus)
   1. Related to hepatitis G, yellow fever and dengue virus
   2. Natural targets are hepatocytes and probably B lymphocytes
   3. Binds to CD81 on these target cell types
2. Genome
   1. Single stranded RNA of 9.5kb including 5' and 3' untranslated regions (UTR)
   2. Encodes a single 3011 amino acid polyprotein
   3. This is cleaved into at least 10 structural and regulatory proteins
   4. Nonstructural parts of this polyprotein are cleaved by viral proteases
   5. Host peptidase cleaves structural proteins from the polypeptide
   6. Viral helicase, polymerase (reverse transcriptase), protease critical to function
3. Replication
   1. The HCV reverse transcriptase has no proof reading activity
   2. Multiple mutations occur, often in the N terminal portion
   3. Likely that ~50% of hepatocytes harbor virus (not all replicating)
   4. About 10 trillion HCV particles produced per day
4. Receptor for HCV is CD81, a tetraspanin protein on hepatocytes and B cells
5. At Least 6 Different Genotypes
   1. Genotypes 1a, 1b - most prevalent serotype, ~75% of cases in USA and Europe
   2. Genotype 2 - second most prevalent in USA and Europe (10% of cases USA/Europe)
   3. Genotype 3 - often associated with cryoglobulinemia (10%)
   4. Genotype 4 - Egypt
   5. Genotype 5 - South Africa
   6. Genotype 6 - Southeast Asia
   7. More than 50 serotypes have been identified
   8. Genotype 1 found in ~98% of blacks in study in USA [47]
6. Liver Damage
   1. Virus is able, in most cases, to circumvent host immune system
   2. Virus can cause direct hepatocyte cytotoxicity
   3. Induction of inflammation with hepatic infiltrates
   4. Of all the hepatitis viruses, causes the most damage in immunocompetent hosts
7. Oncogenesis
   1. HCV appears to have a direct oncogenic effect (mainly on liver cells)
   2. NS3 protein may cause cell transformation

C. Disease Entities and Associations

1. Acute Infection
   1. Usually asymptomatic
   2. In some infected persons, mild symptoms manifest within 7-8 (range 2-26) weeks
   3. Symptoms, when they occur, are jaundice, malaise, nausea
2. Fulminant Hepatitis
   1. Extremely rare with acute HCV infection alone
   2. However, superinfection with Hepatitis A Virus increases risk of fulminant failure
3. Chronic Viral Hepatitis
4. Fibrosis and Cirrhosis [4]
   1. 40% of asymptomatic infection is histologically active and progressive
   2. Severity of disease correlates with ALT elevations, increases with age
   3. 50% of chronic HCV develop fibrosis over 20 years
   4. 20-30% develop cirrhosis over 20 years
   5. Alcohol, HIV, other liver toxins increase risk of cirrhosis
   6. Male sex and older age at infection also increase risk of cirrhosis
   7. Cirrhosis may occur in presence of normal transaminase levels
   8. Without treatment, ~30% will never progress to cirrhosis (or do so over >50 years)
   9. Prolonged HCV response to IFNa associated with improvement in hepatic fibrosis [10]
5. Hepatocellular Carcinoma (HCC) [10]
   1. HCC develops almost exclusively with chronic HCV+ active hepatitis and cirrhosis
   2. In HCV+ cirrhotic patients, ~40% developed HCC within 7 years prior to IFNa use
   3. Currently, 25-30 year latency between HCV+ and HCC in HIV negative persons
   4. Overall risk of HCC in HCV carriers is 1-4% annually or ~10% in 5 years [13]
   5. IFNa reduces risk of chronic HCV infection induced HCC by ~50%
   6. Alpha-fetoprotein (AFP) screening at 6 month intervals has been advocated to detect HCC
   7. Sensitivitive of AFP for detecting HCV induced HCC is likely only ~50% [13]
   8. AFP coupled with liver ultrasound should be used to detect screen for HCC in chronic HCV
6. Autoimmune Hepatitis
   1. May have LKM1+ antibodies (Ab) with hepatitis C infection
   2. Combination viral and autoimmune disease has been described
   3. May also occur with cryoglobulins and other gammopathies
   4. Antinuclear Ab (ANA)
   5. Anti-smooth muscle Ab
7. B Cell Non-Hodgkin Lymphoma (NHL) [14,15]
   1. HCV found in ~37% of patients with B cell NHL and in ~9% of control subjects
   2. HCV associated with ~25% increased risk of NHL overall
   3. HCV associated with ~3X increased risk of Waldenstrom's macroglobulinemia
   4. Also associated with mixed cryoglobulinemia
   5. HCV infection does not appear to affect prognosis of NHL B cell lyhmphomas
   6. HCV is not associated with MALT (mucosa-associated lymphoid tissue) lymphomas
   7. Associated with splenic lymphoma with villous lymphocytes [16]
8. Cryoglobulinemia (see below)
9. Thyroid Disorders [37]
   1. Hypothyroidism 13%
   2. Elevated TSH levels in HCV+ patients versus general population
   3. Autoimmune thyroiditis - antithyroglobulin (17%), anti-thyroid peroxidase (21%) antibodies
   4. Thyroid Cancer [17]
10. Possible Associations
    1. Mooren corneal ulcers
    2. Type 2 Diabetes - risk increased >3 fold [18]
    3. Sicca syndrome
    4. Porphyria Cutanea Tarda
11. Viral Coinfections
    1. Coexisting HBV infection may exacerbate HCV and reduce resopnse to IFNa [19]
    2. HCV coinfection with HIV is a poor prognostic factor for HIV disease [20]
12. HCV does not affect kidney transplant patient graft function or mortality

D. Gammopathies and Cryoglobulinemia [15,50]

1. HCV is the major cause of mixed cryoglobulinemia
   1. HCV binds to CD81 on early stage B lymphocytes (IgM producers)
   2. >80% of patients with type II cryoglobulinemia have HCV infection
   3. High (>90%) prevalence of HCV Abs in patients with essential mixed cryoglobulinemia
   4. Cryoglobulins complex with HCV antigens and HCV Abs
2. HCV Serotypes and Cryoglobulinemia
   1. 36% of patients with hepatitis C have positive cryoglobulins independent of serotype
   2. HCV Genotype III is most commonly associated with cryoglobulinemia
3. HCV and Monoclonal Gammopathies (MG)
   1. 11% of patients with HCV had MG on SPEP
   2. In this study, Genotype 3 was higher in patients with MG
   3. In comparison, only 1% of patients with chronic liver disease (non-HCV or HBV) had MG
4. Rheumatoid Factor is found in the sera of ~70% of HCV positive patients
5. Bcl-2 Role in Lymphoproliferative Disorders
   1. Rearranged Bcl-2 genes t(14;18) most common finding in human lymphomas
   2. 76% of HCV+ patients with mixed cryoglobulinemia had bcl-2 rearrangements
   3. bcl-2 rearrangements more common in Type II (85%) than Type III (65%) disease (all HCV+)
   4. High ratio of bcl-2 to Bax in patients with bcl-2 rearrangement
   5. Bcl-2 rearrangement disappeared after therapy
6. Symptoms of Cryoglobulinemia [50]
   1. ~10-15% of patients with cryoglobulins and HCV are symptomatic
   2. Weakness, arthralgias and purpura most common
   3. Fever may be present
   4. Pulmonary symptoms: non-productive cough, dyspnea
   5. Neuropathy and/or renal dysfunction can occur fe. May contribute to renal dysfunction due to glomerulonephritis
7. Renal Dysfunction
   1. Usual pathology is membranoproliferative glomerulonephritis
   2. Membranous glomerulonephritis also occurs
   3. Hypocomplementemia also found in HCV+ patients with renal disease
   4. Rapid renal deterioration can occur and emergent plasmapheresis required [50]

E. Evaluation [22]

1. Test ANY patient at high risk for HCV and/or with abnormal liver function tests (LFTs) [48]
2. History and Physical
   1. Risk factors for HCV: intravenous drug abuse (IVDA)
   2. Less likely risk factors: unprotected sex, blood transfusion
   3. Evaluate specifically signs of liver disease
   4. Diagnosis is now made based on presence of HCV Ab and then viral load determination
   5. Routine general screening for HCV not recommended [23]
   6. Screening in high risk populations of unknown benefit
3. Serum Chemistry
   1. LFTs for cell necrosis: ALT (SGPT), AST (SGOT)
   2. LFTs for congestion: Alkaline phosphatase, 5' nucleotidase (5'NT), GGT, bilirubin
   3. Prothrombin time (PT) is best marker of acute changes in liver synthetic function
   4. Albumin and transferrin are good markers for longer term liver synthetic function
   5. Serum chemistries do not reliably predict presence of cirrhosis
   6. Renal function must also be assessed
   7. Consider evaluation for monoclonal gammopathy or cryoglobulinemia
   8. TSH levels should be assessed given high rates of hypothyroidism [37]
4. Immunological Virus Detection
   1. Second or third generation ELISA tests
   2. Indeterminant tests (midrange positivity) are tested in immunoblot assay (RIBA II)
   3. Sensitive recombinant protein immune binding assay (RIBA) of several Hep C proteins
   4. Binding to two or more of HepC proteins in RIBA is considered positive
   5. Virus may be associated with Anti-LKM 1 antibodies
   6. Anti-HCV Ab+ and HCV RNA negative likely have cleared infection (10-20%)
   7. All patients with positive immunological HCV test should be confirmed with HCV RNA [21]
5. Viral Load
   1. HCV RNA level and genotyping should be used to confirm all HCV infections [21]
   2. Pretreatment viral load does not predict prognosis (but does affect response rate)
   3. Patients with HCV Abs should have viral load assessed (~10% will be negative for RNA)
   4. PCR based assay is most sensitive to date, more so than branched chain DNA assay
   5. However, branched chain DNA assay has better dynamic range
   6. No consistent ranges allowing comparisons of different test methods
6. Screening for HCC
   1. Important for patients with unknown duration of HCV infection
   2. Also critical in patients with persistent viral loads after treatment
   3. Alpha-fetoprotein and liver ultrasound recommended every 6-12 months
7. Liver Biopsy
   1. Liver biopsy is the only real method for detecting cirrhosis or fibrosis
   2. Biopsy proven cirrhosis found in 20% of chronic HCV+ with near-normal ALT levels [24]
   3. A panel of 6 biochemical markers of liver function and fibrosis may predict biopsy results in some patients with HCV infection [25]
   4. Biopsy may aide in decision to treat for patients who do not meet clear criteria for therapy
   5. In general, all candidates for treatment should undergo liver biopsy unless contraindicated

F. Pathology of Liver Lesions in Chronic HCV

1. Chronic Hepatitis (Persistant)
   1. Portal lymphoid hyperplasia
   2. Focal hepatocyte death
   3. Preservation of limiting plate
2. Chronic Active Hepatitis: piecemeal (± bridging) necrosis and parenchmal inflammation
3. Cirrhosis
   1. Nodular formations with active hepatitis and fibrosis
   2. Fibrosis with active regeneration of "isolated" liver nodules required
   3. May occur normal LFTs [24]
4. Fibrosing cholestatic hepatitis [53]
5. Hepatocellular Carcinoma
6. Inflammatory (hepatitis) lesions are classified as mild, moderate, severe

G. Therapy Overview [1,2,26,27]

1. Acute HCV Exposure (within 4 months) [1,5]
2. Standard of care for chronic HCV is pegylated-IFNa (PEG-IFNa) plus ribavirin [1,28,29]
   1. Many patients cannot tolerated standard IFNa chronically
   2. Newer pegylated IFNa therapies are better tolerated and have higher response rates
3. Indications for IFNa-Ribavirin Combination (Standard) Therapy [29]
   1. Chronic HCV with elevated LFTs
   2. Normal LFTs and normal liver biopsy should generally not be treated
   3. Normal LFTs with mild LFT elevation and normal liver biopsy - optional treatment
4. Monitoring Treatment
   1. Goal is achievement of sustained viralogic response (SVR)
   2. SVR is defined as complete absence of virus by PCR 6 months after cessation of therapy
   3. Undetectable levels by PCR are usually <50-100 copies/mL
   4. Currently, PEG-IFNa+ribavirin provides best SVR, 50-60% of HIV negative patients
   5. SVR is associated with reduction in liver failure in all HCV patients, including those with chronic HCV and advanced fibrosis [52]
5. Treatment Efficacy [29]
   1. Treatment reduces viral load as well as complications of HCV infection
   2. IFNa treatment leading to SVR reduces risk of HCC >90% in patients with chronic HCV
   3. Treatment of HCV+ patients with splenic lymphoma with villous lymphocytes using IFNa±ribavirin led to complete remissions of this NHL subtype [16]
   4. IFNa therapy for cirrhotic HCV associated with reduced risk for developing HCC and improved survival [9]
6. HCV viral RNA levels assessed after 12 weeks [26]
   1. If reduction >2 logs viral RNA, continue therapy
   2. If reduction <2 logs, discontinue therapy
   3. Therapy for genotype 1 is for 48 weeks
   4. Therapy for genotyptes 2 and 3 for 24 weeks
7. Thrombocytopenia
   1. Common with HCV infection and cirrhosis
   2. Platelets <50-70K/µL are a contraindication to IFNa therapy
   3. Eltrombopag is an Orally active TPO receptor agonist
   4. Stimulates platelet counts, even in chronic disease settings
   5. Good activity in thrombocytopenia associated with hepatitis C viral cirrhosis [53]
   6. In patients with HCV associated cirrhosis and thrombocytopenia (<70K/µL platelets), eltrombopag 75mg qd x 4 weeks increased platelets >100K/µL in 95% (0% on placebo) [53]
   7. Side effects similar to placebo, with possibly increased headache

H. Interferon Alpha (IFNa) Therapy [27,32,33]

1. PEG-IFNa 2b or 2a weekly + ribavirin 800-1200mg qd po is standard of care
2. Various Interferons (IFN) approved for HCV [28]
   1. Pegylated IFN (PEG-IFNa; Pegasys®, PEG-Intron®) - prolonged half-life, improved efficacy
   2. IFN alpha (IFNa) 2a (Roferon®)
   3. IFNa 2b (IntronA®, others)
   4. Consensus IFN (Type 1 Interferon, IFNc)
   5. HCV standard treatment is PEG-IFNa with ribavirin for 48 weeks (see below)
   6. Prolonged treatment (18-24 months) may improve long term outcome
   7. Low viral RNA levels (<2-3 million/mL) associated with best responses
   8. Genotypes 2 and 3 have good responses after 24 weeks
   9. Genotype 1 requires 48 weeks for maximal responses
3. PEG-IFNa [27,33]
   1. PEG is polyethylene glycol, a macromolecular polymer of ethylene glycol
   2. Attaching proteins to PEG groups increases half-life of the protein (delays clearance)
   3. This increases the plasma concentration-time curve (AUC)
   4. PEG-IFNa 2b (PEG-Intron®) dosed by weight: 40-120 mcg/kg (see prescribing instructions)
   5. PEG-IFNa 2b is given once weekly (qw) and is more effective than Intron-A in HCV
   6. PEG-IFNa 2a (Pegasys®) - IFN-2a on 40K PEG molecule, 180 mcg sq (abdomen or thigh) qw
   7. PEG-IFNa 2a 180µg once weekly and is more effective than IFNa [34,35,36]
   8. Overall PEG-IFNa 2b+ribavirin leads to 50-60% SVR
   9. PEG-IFNa+ribavirin treatment of genotype 1 for 48 weeks, genotypes 2 or 3 for 24 weeks
   10. PEG-IFNa+ribavirin provided higher responses in non-Hispanic whites than in blacks (52% versys 19%) [47]
   11. PEG-IFNa2b is superior to standard IFNa2b when combined with ribavirin in HIV+ patients infected with HCV [49]
4. Treatment of Acute HCV Infection [1,5]
   1. IFNa-2b 5MU sc daily for 4 weeks, then 3X/week for 20 weeks
   2. Can eradicate virus and is strongly recommended
   3. Unclear if addition of ribavirin in this setting provides added benefit
5. Factors Predictive of HCV Response to IFNa
   1. Viral Serotypes (see below)
   2. Young Age
   3. Absence of cirrhosis; minimal amounts of hepatic fibrosis
   4. Low HCV RNA levels
   5. Low hepatic iron stores
   6. Coinfection with HGV does not affect severity of HCV disease or IFNa response
   7. Coinfection of SEN D or SEN H virus with HCV reduces IFNa/ribavirin response [38]
   8. Persistently normal ALT and negative HCV RNA for 6 months after IFNa therapy [32]
6. Very Common (>30%) Side Effects of IFNa [1,2]
   1. Flu-like syndrome, headache >50%
   2. Fever, rigors
   3. Myalgia
   4. Thrombocytopenia (increased with PEG-IFNa)
   5. Thrombocytopenia associated with HCV can be treated with eltrombopag (see above) []
   6. Induction of autoantibodies - anti-IFNa, anti-thyroid, anti-platelet, anti-RBC Abs
7. Common (1-30%) Side Effects of IFNa
   1. Anorexia
   2. Injection site erythema
   3. Insomnia
   4. Alopecia
   5. Difficulty concentrating
   6. Emotional lability
   7. Depression
   8. Diarrhea
   9. Autoimmune disease (particularly thyroiditis)
   10. Leukocytopenia
   11. Taste perversion
8. Uncommon (<1%) Side Effects of IFNa
   1. Polyneuropathy
   2. Paranoia or suicidal ideations
   3. Seizures
   4. Diabetes mellitus
   5. Retinopathy
   6. Optic neuritis
   7. Hearing impairment
9. IFN ß and consensus IFN have no advantage over IFNa
10. Many patients do not tolerate a 48 week course of full dose INFa or PEG-IFNa

I. IFNa + Ribavirin Therapy [27,29,32,46]

1. Ribavirin
   1. Synthetic nucleoside with little single-agent anti-HCV activity
   2. Adding ribavirin to IFNa based therapy improves SVR by 10-20%
   3. Dose high for genotype 1: 1200mg qd for >75kg; 1000mg qd for <75kg patients
   4. Dose 800mg po qd for genotypes 2 or 3
   5. Ribavirin alone has no real anti-HCV clinical activity [29,30]
2. Ribavirin Side Effects
   1. Very Common (>30%): Hemolysis, nausea
   2. Common (1-30%): Anemia, pruritus, nasal congestion
   3. Uncommon (<1%): Gout
3. Combined IFNa and Ribavirin [29,45]
   1. Standard of care for HCV is PEG-IFNa once weekly + ribavirin 800-1200mg qd
   2. Genotype 1 is treated with high dose; genotype 2 or 3 with low dose ribavirin as above
   3. Genotype 1 treated for 48 weeks; genotypes 2 and 3 treated for 24 weeks [51]
   4. Overall PEG-IFNa + ribavirin for 48 weeks provides undetectable HCV RNA levels in ~50%
   5. In HIV+ HCV+ patients, PEG-IFNa+ribavirin for 48 weeks has undetectable HCV in 27-40% [43,44]
   6. Improvement in liver histopathology observed in majority of patients, even those without complete virologic response [44,45]
   7. May improve membranoproliferative glomerulonephritis (with cryoglobulinemia) [39]
4. Previous IFNa Only Therapy
   1. IFNa+ribavirin is more effective than IFNa alone in previously nonresponsive IFNa [40]
   2. Combination ribavirin + IFNa effective in patients who fail or relapse after IFNa
5. HCV Genotype and Response [46]
   1. Therapy may be stopped at 24 (but not 16) weeks for Genotypes 2 or 3 [51]
   2. In patients with genotypes 2 or 3 who have negative HCV RNA within 4 weeks, combination therapy may be stopped after 12 weeks (rather than 24 weeks) [41]
   3. Continue therapy for genotype 1 for 48 weeks total
6. Viral load <2 million copies/mL associated with higher response rates than higher levels
7. Ribavirin capsules can be obtained by calling 888-347-3416 or 800-927-4227 in USA

J. Liver Transplantation [42]

1. HCV associated cirrhosis is a leading indication for liver transplant
2. Transplant may be offerred to patients with endstage cirrhosis
3. Indictions for Transplant
   1. Hyperbilirubinemia
   2. Intractable Ascites
   3. Spontaneous Bacterial Peritonitis (SBP)
   4. Synthetic Dysfunction: Coagulopathy, Hypoalbuminemia
   5. Hepatorenal Syndrome
   6. Bleeding esophageal or gastric varices
   7. Encephalopathy
   8. Severe malnutrition
   9. Hepatopulmonary Syndrome
   10. Unacceptable quality of life (malaise, weakness, cholestasis)
4. Survival Rates at 3-5 years
   1. Five year survival rates were 62-70% [42]
   2. These rates are ~10% less between HCV positive and negative patients [42]
   3. All transplanted livers are reinfected with HCV
   4. Immunosuppression does not appear to increase HCV virulence

K. Other Therapies

1. Immune Serum Globulin [23]
   1. Prepared from unscreened donors (not from HCV screened donors)
   2. Contains HCV neutralizing antibodies
   3. Protects against HCV transmission by about 85%
2. Antiretroviral therapy reduces liver-related mortality in HIV/HCV coinfection [7]
3. Ineffective Therapies
   1. Glucocorticoids (does not worsen disease used during short courses)
   2. Acyclovir
   3. Thymosin - no benefit in patients who previously received IFNa
   4. Interferon gamma

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