Perspectives on Viral Load

Viral Load Testing

INTRODUCTION
Perspectives on Viral Load (HIV RNA) and When to Initiate Therapy

By Jules Levin, Executive Director of NATAP

The quantitation of plasma viral RNA (commonly referred to as viral load) has provided valuable insights into the pathogenesis of HIV disease and activity of antiviral drugs, including protease inhibitors.

We need to define more clearly the correlates between plasma viral RNA, antiretroviral activity and clinical outcome or efficacy of a therapy. There is some missing information, which will be reviewed today, that we need to better understand the use and interpretation of viral load measurements.

Plasma RNA measurements will have an important role in the clinical treatment decisions doctors and other health providers will be making with HIV infected individuals.

Today, I will give some background and recommendations that are designed to give you some guidelines and guidance to understanding the use and interpretation of viral load measurements.

The following considerations will be addressed today:

what does an HIV-1 RNA level mean?
what constitutes a meaningful change in HIV-1 RNA level?
do changes in HIV-1 RNA level have the same clinical meaning for persons with high compared to those with low HIV-1 RNA levels?
what are the cost-to-benefit considerations in driving the virus load to "as low as possible?"

Without going into much detail about the technologies involved, there are two current approaches to measuring viral RNA:

branched DNA (bDNA) assay, which is based on a signal amplification
technology;
RT-PCR is based on the reverse transcriptase methodology of amplifying the viral target; the AMPLICOR HIV-I MONITOR test which uses this method is commercially available
two other methods, the NASBA or QC-PCR assays (quantitative competitive PCR), are available as research tests; they all share a common methodology of amplifying the viral target.

An important principle in this disease is that individuals who become HIV-infected establish an equilibrium between their host immune system and their virus within the first 6 to 12 months of infection. Dr. Coombs described three different groups characterized by the course of the progression of their disease, into one of these three which individuals may fall. Each of the 3 groups was represented on a graph (displayed by Dr. Coombs) depicting the course of that group's progression to AIDS. In the first group, individuals contain the virus effectively, have very low viral load levels (the equilibrium setting their viral load level at well under 10,000 RNA copies within the first 6 to 12 months of infection), and the graphic depiction of the course of their viral load measurements may remain very flat over the course of many years, possibly extending 10 years, and defines a slow-progressing group of patients. The second group does not contain the virus very well and is characterized by having very high viral load levels (100,000 or higher) within the first 6 to 12 months of infection, and they progress very rapidly to an AIDS defining illness, as early as three years after HIV infection.

The third group is in between, with between about 10,000 to 100,000 RNA copies, and patients falling into this group show an intermediate progression rate. The graph line depicting this group slowly ascends from the 6-12 month post sero-conversion period to 7 or 8 years out and depicts this intermediate rate of progression of the disease. As you can see, not all patients start off with low levels and progress to high levels as the disease progresses.

FDA concerns. If you take a patient's viral load measure at any point along the line of the course of their disease to assess their risk of progression, and if you lower their RNA measure with therapy--- the question that is not yet answered is---if you lower that RNA level to say 10,000 do you indeed alter the course of their disease progression? Will the future course of the progression of that person's disease be the same as a person whose viral load was at that level (10,000) prior to therapy? We don't yet know the answer to this question, but we surmise that will occur, i.e. that lowering of viral measure will alter the clinical course of the individual's disease--delay progression and prolong life. The FDA wants a study to address this question. The FDA's very recent approval of the RT-PCR test is for prognosis. In order to approve the tests for "monitoring clinical therapy", the FDA wants a study(s) that examines individuals who make therapy changes vs. those who don't make therapy changes, after detecting viral load increases. The studies described below do not examine this question, but they study prognosis. However, many doctors and people with HIV/AIDS are using the tests for "monitoring clinical therapy', despite the FDA's limited approval. The FDA stated, in their approval language for the RT-PCR test, --"the test has also been used as an aid in assessing viral response to antiretroviral treatment as measured by changes in HIV-1 RNA levels". A few published papers, in the last year or so, highlight Dr. Coombs' principle. Following is data from a Mellors paper published in the Annals of Internal Medicine 1995; 122: 573-579, that looks at individuals in the Pittsburgh portion of the MACS group.

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About the author: Jules Levin is the Executive Director of NATAP, based in New York City.

The National AIDS Treatment Advocacy Project (NATAP) is a New York State non-profit corporation dedicated to facilitating the effort for development of effective treatment for HIV.

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