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Guide to Hepatitis B for People Living With HIV

June 2009

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Section 5: Diagnostics

Since the discovery of HBV, researchers have identified various ways to measure the rate of viral replication; signs of liver inflammation; degrees of liver damage; different strains of HBV; and evolution of chronic disease. Together, these tests can help identify which phase of chronic HBV disease you might be in, and are essential tools for monitoring disease progression and guiding treatment decisions.

HBeAg (Hepatitis B "e" Antigen)

HBeAg is a protein produced during the HBV replication process, then released into the bloodstream from infected liver cells. People infected at birth who have detectable HBeAg in the body (known as being HBeAg-positive) are in the first two phases of chronic HBV (immune tolerant to immune clearance), and most of them are younger than 35.

During the immune clearance phase, the immune system can develop antibodies to HBeAg (anti-HBe) to get rid of HBeAg in the blood. This is called HBeAg seroconversion (converting from positive to negative; at this point, HBeAg is no longer detectable in the blood) and is one indication that the immune system is gaining control over HBV. HBeAg status should be checked every one to two years to watch for HBeAg seroconversion.

HBeAg seroconversion happens at about 2.15% per year without treatment, and two-thirds of those who have seroconverted can remain that way and will not have disease progression nearly a decade later, greatly reducing their risk of serious liver damage.

HIV-positive people are less likely to have HBeAg seroconversion. The rate is reduced by about 60% as compared to people without HIV, at 3% in two years, and 11% in five years. HIV-positive people are also more likely to revert to being HBeAg-positive than are people without HIV.

The presence of HBeAg was first thought to be a clear indication of active HBV replication. More recently, however, researchers discovered HBV mutations (called pre-core and basal-core mutations) that are capable of replication without also making HBeAg. People with a detectable HBV viral load who are HBeAg-negative have likely developed these mutations. Researchers believe these mutations are more likely to develop with longer duration of HBV infection, as they are usually detected in people older than 40 who were infected at birth. People with these mutations have an increased risk for HBV reactivation and serious liver damage.

Regular Monitoring Tests for Chronic HBV

It is very important to get regular blood tests to monitor HBV progression. These tests can determine when a person should start HBV treatment, thereby preventing or delaying liver damage or liver cancer. Doctors check for two main indicators: activity of the hepatitis B virus (by measuring the amount of HBV in the blood [HBV DNA]) and amount of liver inflammation (by measuring the level of a liver enzyme [ALT]). HBV-DNA and liver-enzyme levels can fluctuate, so one-time measurements don't provide enough information for a definitive diagnosis on the phase of HBV disease or indicate the need for treatment. These tests need to be performed regularly (every three to six months) in order to show persistent elevations, a clearer indication of active viral replication and corresponding immune activation.

HBV DNA (Viral Load)

This test finds and measures the amount of HBV in the blood. Viral load can range from undetectable (not enough to show up on the test) to very high (up to billions of HBV in one drop of blood). A high viral load means the virus is actively replicating. Viral-load levels differ depending on the phase of chronic HBV disease. People who are HBeAg-positive generally have a higher viral load than people who are HBeAg-negative.

HBV viral loads are measured in International Units per milliliter (IU/mL); sometimes they are also reported in number of copies. Different labs use different viral-load tests, and there are differences in conversion rates from copies to IU. As a rough guide, five copies converts to one IU. Check with your lab to find out their exact conversion rate.

  • A viral load greater than 20,000 IU/mL (100,000 copies) is considered high in HBeAg-positive people;
  • A viral load greater than 2,000 IU/mL (10,000 copies) is considered high in HBeAg-negative people.

While a high viral load does not in itself cause liver damage, a recent large-scale and longterm study from Taiwan has shown that people with higher viral loads are more likely to develop cirrhosis and liver cancer later in life. Although there are some limitations to the study (only Chinese patients, most of whom had genotypes B and C exclusively, were studied), this finding has elevated the importance of HBV viral load in predicting disease progression, and viral suppression (lowering the viral load) is becoming a significant treatment goal.

To get a better picture of chronic HBV disease in addition to viral load, people will also need other important tests -- those that measure liver-enzyme levels.

Liver Enzyme Tests: ALT and AST

Liver enzymes are proteins that have specific functions. When the liver is injured, some of these enzymes leave the liver and enter the bloodstream. Several things can cause liver enzyme levels to rise abnormally, such as liver toxicity from prescription and over-thecounter medications, herbs, vitamins, and supplements; exposure to toxic fumes; heavy alcohol consumption; acute or chronic viral hepatitis; and detoxifying from drugs and/or alcohol. Many HIV medications cause liver enzyme elevations.usually not to dangerous levels. In some cases, people may need to switch or discontinue certain drugs.

Liver enzymes are measured through a group of blood tests. Although they are often referred to as Liver Function Tests (LFTs), these tests do not actually measure how well the liver is working.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are two important liver enzymes.

ALT is an enzyme that usually resides inside the liver; it is released from the liver into the bloodstream when liver cells are injured. Increases in ALT are usually a signal of liver inflammation or damage; however, since liver-enzyme levels often fluctuate, ALT levels are not a reliable predictor of disease progression, nor do they indicate the severity of liver disease. ALT levels are also influenced by age, gender, and body weight. HIV-positive people may also develop liver damage when they have low or near-normal ALT levels.

ALT levels should be monitored every three to six months, since persistently increasing levels may suggest HBV disease progression. It's especially important for coinfected people on treatment.or taking any other drugs known to be hard on the have liver enzyme levels measured routinely.

AST is made in the heart, intestines, and muscles, so it is not a sensitive marker for liver injury. AST levels are often used to monitor liver inflammation and damage (in combination with other tests). In monitoring of chronic HBV progression, ALT is used instead of AST, although these tests are usually done together.

ALT is measured in U/L (units per liter). Normal ALT levels are different in men and women, and liver inflammation is indicated by ALT levels above the upper limit of normal (ULN). Individual laboratories set their own ULN levels, but recently researchers have recommended a standardized and slightly lower ULN to more accurately reflect inflammation:

  • ULN for men: ALT = 30 U/L
  • ULN for women: ALT = 19 U/L

The results of an ALT test alone, however, are not enough to decide if someone needs treatment.

  • An elevated ALT level might be due to liver inflammation from causes other than HBV, such as drinking alcohol or taking some drugs and herbs; and
  • A normal ALT level doesn't always mean the liver is healthy; there might be existing liver damage but no elevated ALT because there is no current inflammation (25% of people with normal ALT levels may have existing liver fibrosis).

Liver-enzyme levels often fluctuate or are persistently elevated in people with chronic HBV. Sometimes these fluctuations are referred to as HBV flares or liver enzyme flares. Low-level flares often will cause no symptoms and might not cause liver damage; it is very high levels, persistent elevations, or dramatic changes that doctors are concerned about.

Liver-enzyme levels may be elevated during HBsAg- or HBeAg seroconversion, either spontaneously or during treatment, sometimes to very high levels (more than ten times the ULN). But liver-enzyme levels usually fall back within the normal range shortly after seroconversion. Studies have also shown that HBV treatments are more effective in people who have elevated ALT levels when they start treatment.

In the previous section on HBV natural history, we discussed the four phases of chronic HBV disease. The following graphic illustrates how test results on HBeAg, HBV viral load, and ALT are used to determine which phase of chronic HBV you are in and when treatment is indicated.

Chronic HBV Disease Progression

Click image to enlarge.

Other Liver Enzymes: ALP, GGT, Bilirubin, Albumin, and Prothrombin Time

It is important for people with HBV and HIV/HBV to undergo routine monitoring of ALP, GGT, bilirubin, albumin, and prothrombin time. Results from each test should be evaluated in relation to other information.

Alkaline phosphatase (ALP) is present in tissues throughout the body, including the liver. Many different conditions can cause increased ALP levels in the bloodstream. Elevated ALP may be a sign of blocked bile ducts (cholestatis). Some medications, including the HIV protease inhibitors atazanavir and indinavir can cause ALP elevations.

Gamma glutamyl transferase (GGT) may be elevated when bile ducts are blocked. GGT elevations may be due to liver disease, and/or heavy drinking, and use of some medications.

Bilirubin is a by-product from the breakdown of red blood cells. Bilirubin levels go up in advanced liver disease (direct bilirubin); jaundice, dark urine, and pale stool are common signals of elevated bilirubin. Some drugs, including the HIV protease inhibitors atazanavir and indinavir, can cause elevated bilirubin levels, but this is indirect bilirubin and does not indicate liver injury.

Albumin is a protein made by the liver. It carries drugs, hormones, and waste products through the bloodstream and maintains fluid levels within the body. Abnormally low levels of albumin can be a sign of serious liver damage or, in HIV-positive people, of malnutrition.

PT (prothrombin time; ProTime) testing measures the amount of time it takes for blood to clot. When the liver is damaged, its ability to make clotting factors is impaired. A prolonged PT interval indicates decreased liver function.

HBV Genotype

There are eight different HBV strains, or genotypes (from type A to type H), distributed worldwide. Due to global immigration patterns, different regions in the world have a variety of genotypes. HBV genotype can affect disease progression and response to some treatments, but research into the significance of HBV genotypes is still ongoing, and current knowledge may still change when new information comes to light. A blood test exists that can tell you which HBV genotype you have. Although this information can be useful, genotype testing is very expensive and is not critical in making treatment decisions in most cases.

Genotype A: Most common in the United States, Northern Europe, India, Africa, Spain, and Brazil. Recent studies have shown that people with genotype A have the best response to immune-based treatment (i.e., pegylated interferon; see Appendix on HBV Treatment for more information).

Genotypes B and C: Most common in Asia and the Pacific regions, and among immigrants and their children from these regions now living in Western countries. In studies from Asia, people with genotype C tend to have more severe liver disease and are at higher risk of developing liver cancer than those with genotype B, but it is not clear if treatment should start earlier in people with genotype C.

Genotype D: Most common in the Mediterranean, the Middle East, and India. People with genotype D develop pre-core mutations at a higher rate than do those with other genotypes, and are at increased risk for HBV disease progression.

Genotypes E, F, G, and H: Studies on these genotypes are lacking. Genotype E is most common in West Africa; genotype F in South and Central America; genotype G in the United States and France; and genotype H in Mexico and South America.

Liver Biopsy

Before recommending HBV treatment, some doctors want to perform a liver biopsy on their patients to get more information on the amount of liver damage their patients have. During liver biopsy, a needle is inserted between the ribs and into the liver to remove a small sample of liver tissue. The sample is sent to a lab, where it is examined under a microscope for cell abnormalities. Liver biopsy is uncomfortable, occasionally painful, and carries a small risk of complications (1.3%), such as puncturing adjoining organs or hemorrhage (bleeding), and a much, much smaller risk of death. Many people with HBV are reluctant to have one. Although some doctors will recommend a liver biopsy, particularly in people with ALT persistently just below the level that clearly indicates liver inflammation, it is not always a requirement for determining HBV treatment.

Still, a liver biopsy is considered the diagnostic gold standard for assessing liver disease because it is the most reliable way to learn both the stage (amount of scarring that has already occurred) and the grade (amount of inflammation, which drives future scarring) of liver disease. It can also identify other causes of liver disease that are not HBV-related.

Interpreting Biopsy Results

There are different systems for measuring liver inflammation and fibrosis. All go from zero to a maximum score; the higher the number, the more inflammation or fibrosis. The Ishak scale measures inflammation on a scale of 0 to 18, and fibrosis on a scale of 0 to 6. The METAVIR scale measures inflammation on a scale of A0 to A3 ("A" is for activity), and fibrosis on a scale of F0 to F4 ("F" is for fibrosis).

Guidelines define mild liver damage as a modified Ishak score of 3 or less, and a fibrosis score of 2 or less; and moderate liver damage as an inflammation score of 4 or more and/or a fibrosis score of 3 to 5. Sometimes your doctor might describe the condition of your liver instead of using a score.

Biopsy, however, is not perfect; it is subject to errors in sampling and in reviewing. Results may be inaccurate when a sample is either too small or comes from a part of the liver that is either less or more damaged than the rest. Samples need to be studied by a pathologist (the person who looks at your biopsy) with expertise in evaluating liver disease. In addition, biopsy is an expensive procedure, though it is covered by Medicaid in the U.S. For these reasons, some doctors might not recommend the procedure, especially if they are not liver specialists.

A biopsy should be performed only by an experienced doctor with a good record of successful biopsies. Also, if your pathologist is not a liver expert, he or she may make an error; ask to have your results reviewed by a pathologist experienced in liver disease. If you are concerned about pain, ask your doctor about your options for pain management during and after the procedure. Ask around, it may be easier to find a good doctor by talking with people who have had a biopsy.

Researchers are looking at less invasive alternatives to biopsy (see below).

When Should You Get a Biopsy?

Having a biopsy can help you make a treatment decision by identifying how much liver inflammation and how much liver damage is present. Despite the discomfort and risk of complications it involves, biopsy is still an important test for assessing the need for treatment and for monitoring HBV progression over time. It is therefore recommended before deciding to start treatment (more frequently for HIV/HBV-coinfected people than for those with HBV alone).

Alternatives to a Biopsy: Non-invasive Markers of Liver Disease

There is new research to see whether results from blood tests instead of a biopsy can be used to assess liver damage. This area of research is important, as it could change how HBV is managed in the future.

Recent studies evaluating combinations of these blood tests suggest they are useful for identifying serious liver damage in HCV- and HBV-infected people, but it remains controversial whether they are yet a reliable substitute for liver biopsy.

Measuring Liver Stiffness ("FibroScan")

FibroScan is a non-invasive approach already showing promising results. FibroScan measures the stiffness of the liver using an ultrasound probe on a vibrating apparatus to create waves and measure their speed. Wave speed reflects liver stiffness; the harder the liver tissue, the more rapidly the waves will pass though it.

Although FibroScan is much less sensitive in detecting mild or moderate liver damage, it is very sensitive to severe damage and can identify people who may need treatment urgently. FibroScan is not painful or invasive, but the machines are expensive and are available in only a few clinics. Furthermore, FibroScan may not be accurate in obese people (body mass index [BMI] over 30). You can find out your BMI at:

Non-invasive Biomarkers of Liver Disease (Blood Tests)

Combinations of blood tests are being used to assess liver damage. These tests are most useful for identifying or ruling out cirrhosis rather than mild-to-moderate liver damage. These tests include:

  • SHASTA Index;
  • FibroTest;
  • Hepascore; and
  • Fibrometer.

Regular Screening for Early Signs of Liver Cancer

People with chronic HBV are at high risk of developing liver cancer, sometimes even if they have no liver damage. Therefore it is very important to regularly (at least once a year) check for signs of liver cancer. The prognosis of liver cancer is much better when it is found early.

The AFP (alpha-fetoprotein) test looks for a type of protein in the blood that can be found at higher-than-normal levels (>10 µg/L) in people who have different kinds of cancers, including liver cancer. Sometimes, however, AFP may be elevated when a person's liver is inflamed even if they don't have liver cancer. In addition, some people with liver cancer may have normal AFP levels, so AFP testing alone is not totally reliable.

Ultrasound testing is the main method used for early detection of liver cancer. More sensitive cancer screening tests are still being developed.

Track Your Lab Work

You might want to bring this worksheet with you to your doctor's appointments and record your lab results. Tracking these results over time will give you a better picture of your HIV/HBV disease progression and can tell you if your treatment is working.

Date     Ranges
CD4 cell countFrom 0 to 1,600 cells/mm3.
HIV treatment is recommended when CD4 falls below 350 cells/mm3.
HIV RNA (viral load)From undetectable to over 1 million copies/mL.
HBV DNA (viral load) From undetectable to over 1 trillion IU/mL
ALTULN (upper limit of normal):
Women: 19 units/L
Men: 30 units/L
ASTWomen: 9.25 units/L
Men: 10.40 units/L
ALPWomen: 30.100 units/L
Men: 45.115 units/L
GGTWomen: <45 U/L
Men: <65 U/L
Bilirubin (direct) mg/dl (U.S.)
0.7 umol/L (SI units)
Bilirubin (total) mg/dl (U.S.)
0.17 umol/L (SI units)
Albumin3.1.4.3 g/dl (U.S.)
31.43 g/L (SI units)
PT11.13.5 seconds (INR < 1.3)
AFP<10 µg/L


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This article was provided by Treatment Action Group.
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