Tests used to evaluate the individual with chronic HBV infection

Activity of liver injury

ALT/AST levels

• ALT/AST compartmentalized in hepatocytes, released to serum with liver cell damage from liver cell injury
• ALT/AST can fluctuate widely in chronic HBV infection
• A single normal ALT/AST does not guarantee inactive infection
• Does not give any information on the degree of liver scarring (fibrosis). That is, cannot tell you if cirrhosis is present or not
• Does not give any information on liver function

Liver biopsy

• Direct visualization of the degree of immune activity (inflammation) and hepatocytes death (apoptosis, necrosis)

Severity of liver fibrosis

Platelet count

• Increasing portal hypertension results in hypersplenism and a falling platelet count
• A low normal platelet count may be the first sign of advanced liver fibrosis
• This is an imperfect test: a higher platelet count does not always exclude the presence of cirrhosis

Liver biopsy

• Direct visualization of the degree of liver fibrosis

Predict risk of ongoing immune damage if untreated (natural history)

Age

• Liver-related complications very unusual in young < 30-35
• Increasing risk of cirrhosis and hepatocellular carcinoma with increasing age > 35-50

Gender

• Women less likely than men to have liver-related complications
• Most large natural history studies have been over-represented by men

Core and "e" Antigen/Antibody status

Viral envelope produced by the S (surface) gene, detectable as HBsAg Polymerase produced by P gene Most new drugs target Pol Nucleocapsid produced by core gene Core is NOT secreted to serum Core antibodies (Anti-HBc) detectable in serum as IgM (acute infection or chronic infection with severe flare) or IgG Leader sequence (pre-core) allows secretion of a longer protein called "e", detectable in serum as HBeAg or "e" antigen. Note – "e" is NOT the envelope HBeAg positive: HBV DNA usually very high: very infectious HBeAg negative: protein no longer secreted in large amounts because HBV DNA is lower: not very infectious. However, HBeAg secretion could also stop if a mutation prevents production of pre-C: HBV DNA can still be high and the individual could still be quite infectious

HBV DNA - Viral load testing

Digene assay used in 1990s not very sensitive: Negative test if viral load under 27,000 IU/mL PCR testing is more sensitive but different test kits gave different results. For example, some report in HBV DNA as copies/mL or Genome Equivalents (GE)/mL New international standard is to report in IU/mL PCR based tests can detect HBV DNA to very low levels, ie 12 IU/mL The HBV DNA can range from very low levels to extremely high levels. It is easier to report these levels using the log scale – just count how man "0s" there are: 1 log - 10 2 logs - 100 3 logs - 1,000 or 1 thousand 4 logs - 10,000 5 logs - 100,000 6 logs - 1,000,000 or 1 million 7 logs - 10,000,000/li> 8 logs - 100,000,000 9 logs - 1,000,000,000 or 1 billion

Determine risk of ongoing liver injury based on understanding of natural history

• Hepatitis B is a lifelong infection characterized by different stages
• No single blood test or combination of blood tests at one point in time can be used to accurately predict what will happen in the intermediate future or distant future
• Several readings in time are needed to know if you are stable in one stage or tansitioning to another stage

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Immune tolerant phase Little or no immune damage or control of HBV, usually in younger individuals <40 years old HBeAg positive HBV DNA extremely high, usually > 8 log IU/mL ALT normal Immune damage phase Immune damage to the liver and yet with limited HBV control, usually ages 20-40 HBeAg positive HBV DNA falling due to immune pressure on virus but still high, usually 4-8 log IU/mL ALT elevated Immune control (Inactive carrier state) Immune control without ongoing liver damage HBeAg negative (anti-HBe positive) HBV DNA low, usually <3-4 log IU/mL ALT normal Ongoing immune damage (HBeAg negative chronic hepatitis) Immune damage to the liver with imperfect HBV control HBeAg negative (anti-HBe positive) HBV DNA high but sometimes can fluctuate to low levels and mimic the inactive carrier state, but HBV DNA usually not lower than 3 log IU/mL ALT always abnormal or fluctuating between normal-abnormal