Treatment Review No. 14; November 1994
Richard Jefferys

What is a surrogate marker?

In HIV disease it's hard to tell if someone is getting sicker unless they have symptoms or infections. Symptoms or infections usually mean the disease has already damaged the immune system. Scientists want to try and find ways to measure how much harm HIV is doing to someones body before these symptoms and infections happen. The number of T4 cells you have per milliliter of blood is used as a surrogate marker of how far HIV disease has progressed. A surrogate is a substitute for something. T4 cell counts are a substitute for symptoms when monitoring the health of someone with HIV.

Why are surrogate markers important?

T4 cell counts give a doctor information on when certain treatments or preventive medications should be prescribed. T4 cell counts are also used in drug trials to measure how well a new drug works against HIV so people who don't have other treatment choices can get a drug without waiting years for proof that it extends life or reduces symptoms. Most drugs currently used against HIV were approved by the government based on the effect they had on T4 cell count.

What was the reason for this conference?

A good surrogate marker should tell us how a person with HIV disease is doing. Unfortunately, T4 cell counts don't always do this. Some people with high T4 cell counts may get symptoms of HIV disease. Some people with very low T4 cell counts feel fine. This conference brought together scientists and activists to discuss how best to use surrogate markers in HIV disease.

The newest surrogate marker being talked about was viral load. Viral load means the amount of HIV in the blood. Two tests can measure how much HIV is in a milliliter of blood by counting copies of HIV RNA. RNA is the part of HIV that makes more virus when it infects human cells. HIV needs two pieces of RNA to work properly, so if there are 100,000 copies of HIV RNA in a milliliter of blood, that means 50,000 pieces (often called particles or virions) of virus.

One test is made by the Roche pharmaceutical company and is called the PCR (polymerase chain reaction) test. The other is made by a company called Chiron and is called the bDNA (branched DNA) test. It is hoped that measuring the amount of virus with these tests will give a better idea of disease progression than just looking at T4 cell count.

Scientists need to prove that the viral load in the blood is connected with how someone with HIV disease is doing. The evidence presented at this conference seemed to indicate that there is a connection, but more research needs to be done.

An advisory panel of scientists, researchers and activists reviewed the different surrogate markers being used in HIV disease. These fall into two categories:

* Markers that try to measure how well the immune system is doing. Scientists call these immunolgic markers. T4 cell count is an immunolgic marker as it gives us an idea of how much damage has been done to the immune system by HIV.

* Markers that try to measure the activity of the HIV virus itself. These are called virologic markers. The amount of HIV RNA in the blood (viral load) is a virologic marker as it looks at the virus directly, not at the damage that it's causing.

One of the problems with viral load measurements is that they're only looking in the bloodstream. HIV often gathers in parts of the body called lymph nodes. Cells of the immune system including T4 cells pass through these lymph nodes as they patrol the body, and can become infected by the HIV virus gathered there. Viral load tests do not measure the amount of virus in the lymph node. One of the experimental tests discussed at this conference involves measuring the amount of virus in the lymph node using a technique called fine needle aspiration. A needle inserted into the lymph tissue removes cells. Further studies of this test are underway to see if it might help give an even clearer picture of HIV disease progression.

Another test being studied that could provide another surrogate marker of disease progression is a lymphocyte function test. Lymphocytes are cells of the immune system. T4 cells are one type of lymphocyte. This test measures how well these immune system cells are actually working. The HIV virus is able to damage lymphocytes so they don't function properly. Using this test, a doctor may be able tell someone not only their T4 cell count, but also information about how well these cells are working. Researchers are working on simplifying this test for wider use.

The advisory panel concluded that at the moment no single surrogate marker can be said to give a 100% accurate picture of the progression of HIV disease. Different markers need to be looked at together. Looking at more than one surrogate marker could give a better overall picture of someones health. The panel also decided that research into surrogate markers should give priority to the new viral load tests because the evidence so far suggests viral load may be the most accurate marker of disease progression in people with HIV.

The advisory panel was asked, "What should people with HIV infection and clinicians caring for them be told about viral quantitation (viral load) now?" They answered that viral load does mark disease progression, but that it is too early to say if this measurement can be used to help make treatment decisions.

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