A

• Acute flare or exacerbation of hepatitis B: Intermittent elevations in hepatic aminotransferases that can occur in chronic hepatitis B, usually more than twice the baseline value and as high as 10 times the upper limit of normal.
• Alanine aminotransferase (serum), upper limit of normal: The upper limit of normal ALT should be considered 30 U/L for men and 19 U/L in women with chronic hepatitis B. This threshold is relevant for both treatment and biopsy decisions when managing this infection. See case, “Deciding to Initiate Antiviral Therapy in Patients with Chronic Hepatitis B Virus Infection.”
• Anti-hepatitis B core antibody (anti-HBc), total: The antibody directed against hepatitis B core antigen - see below under Core antibody for details. Total anti-HBc refers to presence of either IgG or IgM and test result does not discriminate between the subclasses. Its presence in the blood indicates prior or current hepatitis B infection. It does not confer protection against HBV.
• Anti-hepatitis B surface antibody (anti-HBs): The antibody directed against hepatitis B surface antigen. When present at titers that exceed 10 IU, it confers protective immunity against HBV.

B

• Biochemical response: A decline in serum ALT to within the normal range on treatment
• Bridging fibrosis: An indicator of advanced disease characterized by fibrosis that extends to form bridges between portal-vascular structures. It is an important predictor of progression to cirrhosis. When bridging fibrosis is seen diffusely in a liver specimen, it is classified as cirrhosis.

C

• Child-Pugh-Turcotte (CTP) classification: Widely used and published scoring system for liver disease severity. Based on clinical and lab criteria, patients are classified as Class A, B, or C. Those with class C have the most severe liver disease. See Figure 1
• Chronic “active” or “immune active” hepatitis B: Stage of hepatitis B infection characterized by an elevated serum ALT (usually defined as exceeding twice the upper limit of normal) and thought to reflect immune-mediated lysis of infected hepatocytes, often in the setting of HBV DNA level >2000 IU/mL; possibly triggered and maintained by ongoing viral replication.
• Cirrhosis: Describes a condition of the liver characterized by prominent and irreversible scarring. Physical examination or ultrasound findings may suggest a diagnosis of cirrhosis, and some non-invasive tests provide moderately accurate assessment of whether cirrhosis is present. However, ultimately the diagnosis of cirrhosis is based on liver histology and the presence the bridging fibrosis (see above).
• Compensated versus decompensated cirrhosis: The main differentiation between compensated and decompensated cirrhosis depends on Child-Pugh-Turcotte scoring (see above) with Child A being compensated and Child B or C, decompensated.
• Core antibody (anti-HBc): Hepatitis B core antigen (HBcAg) is an intracellular antigen expressed by infected hepatocytes that is not detectable in serum, but antibodies are produced in response to HBcAg peptides (smaller fragments of the HBcAg). These antibodies (anti-HBc) can be detected throughout the course of HBV infection and are a marker of natural exposure to HBV; anti-HBc is absent in those who have been vaccinated. Core antibody is generally in the form of IgM during acute infection or flares of HBV and predominantly in the form of IgG during chronic or resolved infection.
• Core promoter mutations: These mutations in the hepatitis B DNA core region can emerge spontaneously or under drug pressure resulting nucleotide substitutions in the core promoter region that effectively decrease the production of HBeAg. Patients who have these mutations can have active liver disease with high HBV DNA levels after HBeAg seroconversion. See case, “Approach to Hepatitis B e Antigen Negative Patients with Increased Hepatic Aminotransferase Levels.”

D

• Direct-acting antiviral agents (DAAs): DAAs refer to the array of small-molecule compounds that have been designed and are currently being studied to target specific HCV enzymes. Among those furthest along in development include the NS3/4A protease inhibitors and the NS5B polymerase inhibitors.

E

• Early virologic response (EVR): A ≥2 log10 decline in hepatitis C (HCV) RNA level from baseline value by week 12 of treatment. A complete EVR is defined as decline to undetectable HCV RNA level (<60 IU/mL) by week 12; a partial EVR is detectable HCV RNA but ≥2 log10 decline. A failure to achieve an EVR is associated with a high likelihood (>96%) of treatment failure; when this occurs, treatment discontinuation should be considered.
• Encephalopathy: Describes a syndrome of global brain dysfunction characterized by confusion and cognitive impairment. Mild encephalopathy may cause only slight reductions in normal cognitive function whereas severe encephalopathy usually manifests a severe confusion and somnolence, and in extreme cases, coma. Hepatic encephalopathy refers to encephalopathy resulting from liver disease.
• End of treatment response (ETR): Undetectable HCV RNA (<60 IU/mL) at the end of treatment. An ETR is not particularly predictive of a sustained virologic response (SVR) but is necessary for an SVR to occur.
• Extended Rapid Virologic Response (eRVR): Undetectable HCV RNA level (<60 IU/mL) at weeks 4 and 12 of treatment.

G

• Genotypes, HBV: There are 8 genotypes for HBV worldwide, labeled A through H, all of which have been found in the United States. Genotypes A and B are more responsive to interferon-based therapy compared with genotypes C or D, but initial responses to oral antiviral agents appear to be similar across genotypes.
• Gentoype, HCV: Hepatitis C viruses can be categorized into six major genotypes globally. Genotype 1 (subtypes 1a and 1b) is the most commonly isolated genotype in the United States, followed by 2 and 3. Genotypes 4, 5 and 6 are increasingly observed in the US, especially among foreign-born patients from Asia and Africa (see Map). Genotypes 1 and 4 HCV are associated with lower response rates to pegylated interferon and ribavirin compared with genotypes 2 and 3. Treatment responses to genotypes 5 and 6 are not as extensively described but thought to fall somewhere in between response rates of genotypes 1/4 and genotypes 2/3.

H

• Hepatitis B c Antigen (HBcAg): HBcAg is an intracellular antigen synthesized within infected hepatocytes. Most of the HBcAg that is generated is assembled into the viral core (nucleocapsid). Free HBcAg does not not circulate in significant quantity in the blood, but it does circulate as part of the intact hepatitis B virion. HBcAg is not detected on serum tests.
• Hepatitis B e antigen (HBeAg) clearance: Loss of detectable HBeAg from serum, which typically signifies greater immune control of hepatitis B by the host and remission of disease activity, especially if occurs spontaneously (i.e. without treatment) and in context of decreased serum HBV DNA. HBeAg clearance usually precedes HBeAg seroconversion. In acute infection that resolves, the HBeAg is promptly cleared with subsequent development of anti-HBe antibody. This occurs more slowly in those who have chronic persistent infection.
• Hepatitis B e antigen (HBeAg) seroconversion: Loss of HBeAg and development of anti-HBe antibody. In setting of decreased HBV DNA levels and normal ALT, this is usually associated with disease remission.
• Hepatitis B surface antigen (HBsAg): HBsAg exists as the major component of the surface (envelope) of the intact hepatitis B virion and as excess viral envelope in the form of subviral lipoprotein particles (spheres and filaments). HBsAg can be detected in serum 1 to 10 weeks after acute exposure to the virus. In patients who go on to resolve their infection, HBsAg usually becomes undetectable after 4 to 6 months. Persistence of HBsAg beyond 6 months is by definition chronic hepatitis B. Clearance of this antigen with subsequent development of surface antibody (anti-HBs) is a major benchmark but occurs rarely (0.5% or less per year) in patients with chronic infection.
• Hepatitis E antigen (HBeAg): A precore protein secreted into the circulation by hepatitis B virus (HBV)-infected hepatocytes and generally considered a marker of HBV replication and infectivity. The presence of HBeAg is usually associated with high levels of HBV DNA in serum.
• Histologic response: A decline in histologic activity by at least two points on a scoring scale and no worsening fibrosis on liver biopsy compared to pre-treatment biopsy, an outcome typically measured in clinical trial rather than actual practice settings.

I

• IL28B genotype: The IL28 gene encodes interleukin 28, also known as interferon lambda, a cytokine (chemical messenger) with antiviral activity. Investigators discovered that genetic variations of this gene are strongly associated both with spontaneous clearance and sustained virologic response to treatment of hepatitis C. Patients with genotype C/C, for example, are 2.5 times more likely to respond to hepatitis C treatment than those with genotype T/T.
• Immune-tolerant hepatitis B: Typically seen in patients who acquired HBV perinatally, this stage of hepatitis B infection is characterized by HBeAg-positive status, high HBV DNA levels often in million IU/mL range but with normal ALT and the absence of significant ongoing necroinflammatory disease activity on liver biopsy.
• Inactive carrier: Also called a “low-replicative” phase, this stage of hepatitis B infection is characterized by HBeAg-negative status, low HBV DNA levels typically <2000 IU/mL, normal ALT and the absence of significant ongoing necroinflammatory disease activity on liver biopsy.

L

• Lead-in phase: Refers to the initial (typically 4-week) period of HCV treatment where pegylated interferon and ribavirin are started before the addition of the third agent. Boceprevir, for example, requires a 4-week lead-in based on clinical trial design. The lead-in provides the advantage of assessing interferon responsiveness and likelihood of subsequent treatment response in treatment-naïve individuals.

M

• Model for End-Stage Liver Disease (MELD): Used to estimate the survival probability of a patient with end-stage liver disease. The model uses the most recent laboratory tests for serum bilirubin, international normalized ratio (INR), and serum creatinine to generate a "MELD score". The MELD scores range from 6 (less ill) to 40 (gravely ill) and are often used to prioritize patients waiting for a liver transplant.

N

• Necroinflammatory activity: Reflects the degree of inflammation and necrosis seen on liver biopsy in a patient with chronic viral hepatitis – the severity of this activity is characterized by a scoring system (Ishak, Knodell, Metavir are examples). Necroinflammatory activity is one of the main predictors of liver disease outcome in hepatitis B; patients with a high activity score are at greater risk of rapid progression of fibrosis and cirrhosis.
• Non-responder: Failure of the HCV RNA level to drop to undetectable by week 24 of therapy. Treatment should be discontinued in such cases.
• Null responder: A less than 2 log10 decline in HCV RNA levels from baseline value by week 12 of treatment. This is synonymous with an absent early virologic response.

P

• Partial virologic response: A ≥2 log10 decline in HCV RNA levels from baseline value by week 12 of treatment, but HCV RNA remains detectable at week 24 of treatment.
• Precore mutation: These mutations occur in the precore region of the hepatitis B DNA and can emerge spontaneously or under drug pressure. The precore DNA mutations result in a mRNA stop codon that effectively prevents the production of HBeAg. Patients who have these mutations can have active liver disease with high HBV DNA levels after HBeAg seroconversion.
• Primary non-response: A decrease in serum HBV DNA by less than 2 log10 IU/mL after at least 24 weeks of antiviral therapy.
• Protease inhibitors, HCV NS3/4A: Among the first approved class of direct-acting antiviral agents is the HCV NS3/4A protease inhibitor. These drugs inhibit the NS3/4A serine protease, which is responsible for cleaving the HCV polyprotein precursor, an essential step in the HCV viral lifecycle.

R

• Rapid virologic response (RVR): Undetectable HCV RNA level (<60 IU/mL) by week 4 of treatment. This rapid clearance of virus is associated with a high likelihood of treatment success, with up to 80-90% of patients who achieve RVR subsequently demonstrating sustained virologic response.
• Reactivation of hepatitis B: Reappearance of active necroinflammatory disease in the liver in an individual who was known to have resolved hepatitis B or inactive carrier state.
• Response-guided therapy (RGT): RGT is a strategy of following early HCV viral kinetics and adjusting the treatment duration accordingly; this is in contrast to fixed-duration therapy, which has been the standard of care with peg-interferon and ribavirin for genotype 1 HCV infection. When protease inhibitors telaprevir or boceprevir were introduced as part of triple therapy to pegylated interferon and ribavirin, clinical trial data demonstrated that those patients who promptly suppressed their HCV viral level by week 4 of triple therapy and maintained this in subsequent week 8-12 follow-up could benefit just as well from a shorter total duration of treatment (e.g. 24-28 weeks versus 48 weeks).

S

• Sustained virologic response (SVR): Undetectable HCV RNA (<60 IU/mL) 24 weeks after treatment cessation. This is generally a lasting response in the vast majority of patients.

U

• Undetectable viral level, HCV: HCV RNA level that is below the lower limit of detection of a sensitive molecular assay. Previously, the lower limit of detection was typically less than 50 to 60 international units per milliliter (IU/mL). More recently, with the introduction of HCV protease inhibitors, the lower limit of detection in newer assays is 10 to 15 copies/ml.

V

• Viral breakthrough, HBV: Increase in serum HBV DNA of >1 log10 IU/mL above nadir after achieving virologic response, occurring during continued treatment.
• Viral breakthrough, HCV: Reappearance of HCV RNA during treatment, occurring after patient has achieved complete suppression (undetectable HCV RNA level).
• Viral rebound, HBV: Increase in serum HBV DNA to >20,000 IU/mL or above pre-treatment HBV DNA level after achieving virologic response on continued treatment.
• Viral relapse, HBV: Increase in serum HBV DNA of ≥1 log10 IU/mL after cessation of treatment in at least two measurements more than 4 weeks apart.
• Viral relapse, HCV: Reappearance of HCV RNA after an end-of-treatment response and treatment cessation.
• Virologic response, HBV: A decrease in serum HBV DNA to undetectable levels by PCR assays, and loss of HBeAg in patients who were initially HBeAg-positive.