<%@LANGUAGE="VBSCRIPT" CODEPAGE="65001"%> Module 4: The main types of test relevant to the diagnosis and management of HCV

Module 4: Testing and monitoring - section 3

In this document:

The main types of test relevant to the diagnosis and management of HCV

Activity: Large group discussion and presentation
Section Time: Approximately 30 minutes

The main aim of this section is to provide a clear understanding of the purpose of the main types of test that are commonly encountered and to begin to explore some of the options and issues that arise with their use.

Show Slide 4.5 (Group work) :


To facilitate the discussion:

  • This should be done quite quickly just to establish the different types of test
  • Allow the participants to offer their own undirected ideas first
  • Note the specific terminology that people use and any areas that may require clarification during Slide 4.6 (What tests are relevant to HCV?)
  • If people focus exclusively on diagnostic tests, ask then whether they can think of tests for other purposes
  • Within the discussion, encourage people to distinguish testing for diagnostic purposes, monitoring liver damage and determining treatment response

Show Slide 4.6 (What tests are relevant to HCV?) :


To facilitate the discussion:

  • Clarify the purpose of any of the main types of test that have not been mentioned
  • Distinguish the role of tests that a) indicate exposure to the virus b) confirm the presence and severity of active infection c) indicate disease progression
  • Refer to the terminology that was used by participants with the previous slide and clarify any areas of confusion

Show Slide 4.7 (What does European guidance say about testing and treatment for PWID?) :


 

Antibody testing

Show and talk to Slide 4.8 (Antibody testing – serologic assays) :


Key points to cover:

  • What antigens/antibodies are
  • The significance of the window period regarding recent risk behaviours
  • The need for HCV RNA testing in cases where results are anti-HCV positive
  • There are both advantages and disadvantages to testing
  • Best practice requires pre and post test discussion/counselling
Supporting content:

Antibody testing uses serologic assays (measures) to investigate blood serum for evidence of infection by evaluating antigen-antibody reactions.

Antigens are substances (e.g. viruses, toxins and bacteria) that when introduced into the body stimulate the production of antibodies.

Antibodies are immunoglobulin proteins present in the blood serum or body fluids as a result of antigenic stimulus, which only interact with the antigen that induced them or that are closely related.

Enzyme immunoassays (EIAs) are used to detect hepatitis C antibodies (anti-HCV) and screen for and help diagnose HCV infection. Anti-HCV can be detected in the serum or plasma using a number of immunoassays.

Testing now has a high level of sensitivity (ability to accurately identify people who are anti-HCV+ve) and specificity (the ability to distinguish people who are anti-HCV-ve and avoid false positives). False positive results are more likely to occur when testing is performed among populations where the prevalence of hepatitis C is low. False negative results may occur in the setting of severe immunosuppression such as infection with HIV, solid organ transplant recipients, hypo- or aggammaglobulinemia or in patients on haemodialysis.

The recombinant immunoblot assay (RIBA) was originally developed as a more specific, supplemental assay to confirm the results of EIA testing, but with the widespread availability of nucleic acid testing, the role for RIBA testing in HCV diagnosis and management has all but disappeared.

Newer tests have advantages in terms of speed (Rapid Tests) or their reduced invasiveness (Dried Blood Spot).

Rapid tests can provide a result in minutes.

Dried blood spot testing only requires a tiny amount of blood that can be provided from a pin prick, rather than requiring venous access, which is often problematic among PWID whose veins are collapsed/damaged.

  • Hickman M et al. (2008), J Viral Hepat. 2008 Apr;15(4) :250-4. Increasing the uptake of hepatitis C virus testing among injecting drug users in specialist drug treatment and prison settings by using dried blood spots for diagnostic testing: a cluster randomized controlled trial.
  • Tuaillon  E et al. (2010) Dried blood spot for hepatitis C virus serology and molecular testing. Hepatology. Volume 51, Issue 3, pages 752–758,

 

HCV RNA testing

Show Slide 4.9 (HCV RNA testing) :


Key points to cover:

  • A positive HCV RNA test result has important implications for both a) reducing risks to others and b) protecting the person’s own health, which are covered in more depth later.

 

Show Slide 4.10 (HCV RNA tests) :


Key points to cover:

  • Quantitative tests help guide whether treatment should be commenced and measure the treatment response
  • The need for HCV RNA testing means diagnosis is generally a two stage process, which can be problematic for some PWID
  • Genotyping assays determine which type(s) /subtype(s) of HCV are active and further guide the choice of treatment and expected outcome
  • A person’s IL-28B gene also determines how well they may respond to treatment. The CC variant responds best, TT has the poorest response and TC is intermediate
Supporting content:

PCR tests are more commonly encountered but both these and TMA test for HCV RNA and have high sensitivity and specificity rates (98-99%).

Quantitative tests HCV RNA tests measure viral copies/mL or IU/mL (international units). IU/mL is now the preferred WHO standard.

For monitoring purposes, it is important to use the same laboratory test before and during treatment.

 

IL-28B Genotype

Just like the Hepatitis C virus has its own genetic make-up, so do we. An international research effort to sequence and map all of humans' genes - together known as the genome - was completed in April 2003. This discovery gave us the ability to read nature's complete genetic blueprint for building a human being.

The human genome comprises a sequence of approximately three billion parts, called nucleotides, which are organized into DNA molecules. Just four letters represent the nucleotides, which serve as the alphabet for the language of life: A, C, G and T - corresponding to adenine, cytosine, guanine and thymine.

Research presented in 2010 revealed that the coding at a single site on the human genome made a big difference in people's response to Hepatitis C treatment. Known as IL-28B, this site may have either a T or a C on the genome. Since a person inherits two copies of the genome (one from each parent) to make up each allele, individuals may have one of the following alleles at IL-28B:

TT - These individuals were found to have the poorest response to Hepatitis C treatment.
CC - These individuals have the best response to Hepatitis C treatment.
TC - These individuals appear to have a response to Hepatitis C treatment in between those with the TT and CC alleles.

Since the C nucleotides are more common in Europeans than in Africans, it makes sense that those of European descent have a better rate of beating the virus than those of African descent.

http://www.hepatitis-central.com/mt/archives/2010/12/differentiating.html

 

Liver Function Tests (LFTs)

Show Slide 4.11 (Liver function tests - LFTs) :


Key points to cover:

  • LFTs were relied upon more extensively in the past
  • Raised ALT levels are present in 2/3 of those infected but not elevated levels at all in 1/3.
  • Other factors that can increase ALT/AST include side effects from prescription and over-the-counter medications, herbs, vitamins and supplements, exposure to toxic fumes, high alcohol intake, a new or existing hepatitis infection, and coming off drugs and/or alcohol
  • Many HIV drugs can cause liver enzymes to increase—though not usually to dangerous levels. In some cases, those drugs need to be stopped or switched
  • ALT should nevertheless be monitored routinely, as if it continues to increase, it may mean HCV is getting worse.
Supporting content:
Liver enzyme tests: ALT and AST

Liver enzymes are proteins that have specific functions. Some of these enzymes leave the liver and enter the blood when the liver is injured.

People taking HIV drugs (or any other drugs processed by the liver) need to have liver enzyme levels measured with their routine blood tests. This is especially important if they also have HCV. Liver enzymes tests are often called liver function tests (LFTs), although they do not really measure liver function. The results from these tests should be looked at in relation to other information.

AST is another enzyme involved in the production of amino acids but because it is made in the heart, intestines, and muscles, it is not a sensitive marker for liver injury. AST is often used to monitor liver inflammation and damage in combination with other tests.

Other liver enzymes: ALP, GGT, bilirubin, albumin and prothrombin time

It is important for people with HCV and HIV/ HCV to undergo routine monitoring of ALP, GGT, bilirubin, albumin and prothrombin time.

Alkaline phosphatase (ALP) is another enzyme that is present in tissues throughout the body, including the liver. If blood levels of ALP increase, this can be a sign of disease or damage to tissues. Your doctor can also test specifically for ALP from the liver. Some medications, including the HIV protease inhibitors atazanavir and indinavir, can cause ALP elevations. Elevated ALP from the liver is a sign of blocked bile ducts caused by liver disease.

Gamma glutamyl transferase (GGT) is enzyme involved in metabolism that is produced in the bile ducts. `Any type of liver disease, heavy drinking, and some medications can increase levels of GGT.

Bilirubin is a waste-product from the breakdown of red blood cells. The liver is involved with processing bilirubin. When the liver is damaged, it may be unable to process bilirubin, and the total bilirubin levels increase. Jaundice, dark urine and pale stool are common signals of increased bilirubin. Some drugs, including the HIV protease inhibitors atazanavir and indinavir, can cause increased bilirubin levels.

Albumin is a protein made by the liver. It carries drugs, hormones and waste products through the blood and maintains fluid levels within the body. Abnormally low levels of albumin are a sign of serious liver damage.

PT (prothrombin time; pro-time) PT 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. If this time increases – referred to as a ‘prolonged PT interval’ it shows that the liver is not working so well.

Screening for liver cancer in people with cirrhosis

People with HCV cirrhosis are at risk for liver cancer. Regular screening can detect early-stage liver cancer. Usually, screening consists of a liver scan by ultrasound or computed tomography (CT), and a blood test measuring alphafetoprotein (AFP; a protein made in foetal liver tissue) levels. Screening is recommended every six months.

Source for notes above: Guide to hepatitis C for people living with HIV. (iBase 2009)

Show Slide 4.12 (HCV tests and what the results mean) :


To facilitate:

  • Use table based on iBase 2009 to summarise.

Liver biopsy and alternatives

Show Slide 4.13 (Liver biopsy and alternatives) :


Key points to cover:

  • Although assessing inflammation and fibrosis can be diagnostically valuable, it is not essential in all cases.
  • These tests can assist decision-making as to whether treatment should be commenced and what results might be expected.
  • Biopsy is considered to be the ‘gold standard’ for assessing the nature and severity of liver disease, but has some disadvantages compared to the newer FibroScan technique
  • The most common side effect of a biopsy is pain – an estimated 30-50% of patients experience pain. 
  • Complications from biopsy are rare – 1/1,000 biopsies or less.  Potential complications from a liver biopsy include bleeding, bleeding that requires hospitalization or transfusion, puncture of a surrounding organ and death.
  • Although biopsy is the diagnostic ‘gold standard’, FibroScan has considerable advantages in terms of patient safety and acceptability.

 

Show Slide 4.14 (Biopsy results) :


Key points to cover:

  • Fibrosis is the formation or development of excess fibrous connective tissue in an organ or tissue as a reparative process or reaction. See module 3.
  • Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated).
  • A biopsy is helpful for decisions regarding treatment options, the likely benefits, their urgency, or if they should best be avoided.  
Supporting content:

Currently the most accurate way to check the extent of damage to the liver is by biopsy. A liver biopsy is a test in which small pieces of liver tissue are removed and examined under a microscope. This is done via a long needle inserted usually between 8th and 9th ribs under the right arm. The tissue will be assessed to see the extent of inflammation and fibrosis. (A biopsy will also reveal other abnormalities such as damage to bile ducts and the presence of fat). Although biopsy has some advantages, these need to be weighed against its disadvantages, which FibroScan lacks. 

The degree of inflammation is described in terms of inflammatory grade. Fibrosis is described by fibrotic grade. Confusingly there are several different scoring and grading systems for liver biopsies, and the same numbers are not comparable with another system.

The biopsy will indicate which stage of inflammation and fibrosis (scarring) are present in the liver. Inflammatory grade will range from none to extensive inflammation. Fibrotic grade will range from minimal scarring, scarring that has developed outside of the portal tracts, fibrosis that has spread or is bridging towards neighbouring portal tracts is advanced scarring or cirrhosis.

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