AIDS TREATMENT UPDATE, Issue 39, March 1996
Edward King

WHAT IS VIRAL LOAD?

The term 'viral load' is usually used to describe the amount of HIV in a sample of blood. This is measured using tests called quantitative PCR or branched chain DNA. There are now several different tests or 'assays', some made commercially and others prepared by local laboratories.

Although the different tests use slightly different techniques, they all work by looking for HIV's genetic material, RNA. Each 'signal' in the assay is considered to indicate the presence of one HIV viral particle (sometimes referred to as one copy) in the sample.

The result is usually described in terms of the number of HIV RNA copies per millilitre of blood (copies/ml). In HIV-positive people who have not developed symptoms, a viral load higher than 100,000 is considered to be high, and below 10,000 is considered low.

These numbers are often written in a form known as the logarithmic scale, such as 10^5 (which is spoken as 'ten to the power five'). This means that the actual number is 10 x 10 x 10 x 10 x 10. Another way of thinking of 10^5 is as 1 with the decimal point moved five places to the right, which is the same as 1 plus 5 zeros - 100,000.

For each test there is a lower limit, below which it is unable to on is at least as good as the staging systems used to classify the severity of various cancers. They suggested that for untreated people, a single snapshot measure of their viral load can give a good idea of the likely 'natural history' of their HIV infection, identifying those who are at greatest need of anti-HIV therapy.

THE EFFECTS OF TREATMENTS

Other studies examined questions about viral load and anti-viral treatments: - whether a single measurement of the viral load of people taking anti-HIV therapy can predict their risk of disease progression - whether changes in viral load soon after taking an anti-HIV regimen can predict the longer-term effects of the drug(s) on disease progression and survival.

Two studies examined whether a single 'snapshot' measurement of viral load is also useful for predicting clinical outcome among people who are taking anti-HIV treatments - with contradictory results. Researchers examined whether the initial viral load of participants in the American trial ACTG 116A predicted their prognosis. In common with the Pittsburgh study described earlier, they found that the baseline viral load level was a good predictor for people who had never taken anti-HIV treatments. But for participants who had taken AZT before - all of whom had taken it for less than four months - a 'snapshot' measurement of their viral load on entering the study could no longer predict their clinical course. These researchers suggested that the predictive value of a single measurement of viral load may be lost if you have already taken anti-HIV treatments, even for a short time.

By contrast, however, another team of researchers studied 620 people enrolled in two large American trials comparing AZT monotherapy with combination therapy with AZT plus ddC or 3TC. They wanted to know whether a participant's most recent viral load measurement predicted his/her risk of disease progression. Their results suggested that it did: people with higher viral load were at increased risk of progression. This team found that CD4 count measurements were also useful, and that the best way of predicting an individual's risk of developing AIDS was to monitor both tests.

CHANGES IN VIRAL LOAD

However, several trials reported in Washington reported that changes in viral load in response to anti-HIV drugs could give an indication of the likely effectiveness of the treatment. Researchers first measured the viral load of individuals who had not yet started treatment, or who had been on the same anti-HIV regimen for some time. They then compared their viral load a few weeks later, after they had started treatment or changed to a new regimen.

In the past, trials have tended to measure changes in viral load using the log scale; for example, a treatment may be said to have reduced viral load by 1 log. It is important to remember that this is a relative measurement - a one log decrease is a reduction to a tenth of the starting value, such as from 1,000 to 100, or from 10 to 1. This means that it is easier to show a 1 log reduction in viral load among people who have a high initial viral load than in those with lower viral load, simply because they have more virus to start with.

More recently, researchers have started to describe the effects of drugs in terms of the proportion of treated people whose viral load fell below the detectable limits of the assay. This makes it easier to compare the results of different trials, because it is an absolute measurement, not a relative one. The significance of this depends on the viral load level before treatment: if people start with a low viral load, it does not have to fall very much to become 'undetectable'. Also, the lower threshold of different tests does vary, so the same test must be used for monitoring viral load over time.

DELAVIRDINE STUDIES

One study looked at 1,900 people enrolled in two trials of the experimental drug delavirdine. This is a non-nucleoside reverse transcriptase inhibitor, made by Pharmacia & Upjohn under the trade-name Rescriptor, which is being tested in combination with AZT or ddI. In the pooled results from these ongoing trials, people whose viral load had fallen by at least 0.5 log, which is about 68%, after eight weeks of treatment had a much reduced risk of developing AIDS or dying during the 60-week trials. People who did not achieve this decline in viral load after eight weeks were two-and-a-half times more likely to develop AIDS than people whose viral load did fall. Changes in CD4 count were not as good at predicting the effects of treatment.

This effect was seen among all the various 'patient populations' enrolled in the studies. Their CD4 counts ranged from zero to 500 and some had taken AZT before while others were previously untreated. The link between a fall in viral load and an improved prognosis was not an effect of delavirdine specifically - it was also seen among the trial participants who were taking AZT monotherapy or ddI monotherapy.

Some anti-HIV regimens now being tested lead to reductions in viral load that are often much greater than 0.5 log. But the Upjohn researchers said that on average, achieving a 0.5 log reduction after eight weeks has the greatest impact on prognosis. Greater reductions in viral load were linked to an even lower risk of disease progression, but the additional benefits of each additional 0.5 log reduction were relatively small. When their viral load had fallen below 10,000, participants' risk of progression was very low.

ACTG 175

Another study looked at a sub-group of 391 participants in the ACTG 175 trial of combination therapy with AZT plus ddC or ddI. Overall, it too found that people whose viral load had fallen to a tenth of its starting value (a 1 log reduction) after 8 weeks of treatment had a 50 to 60% reduced risk of developing AIDS or dying. Again, after eight weeks of treatment, viral load changes were a much better predictor of clinical outcome than CD4 count changes.

By the time participants had been treated for a year, however, the picture had changed, and CD4 count changes were the better predictor.

IMPLICATIONS

What are the potential implications of the latest research for HIV-positive people in Britain today?

Many people with HIV who have not taken anti-HIV drugs may be more likely to start if they feel that they are at a significant risk of disease progression. The Pittsburgh research suggests that a single measurement of your viral load may provide important information about your prognosis, and so might help with that difficult decision.

Secondly, if you are taking anti-HIV drugs, measurements of viral load might help you and your doctor to assess whether the treatment is working well. Once anti-HIV treatment has begun, it is not yet clear whether a single viral load test can provide useful information about your risk of disease progression. However, changes in your viral load over time do seem to be a good indication; if your viral load starts to rise significantly after some months of taking a certain regimen, you may decide it's time to change to another drug(s). Likewise, if you start a new regimen but see no significant change in your viral load after a couple of months, it may be reasonable to assume that it is not working well.

However, there is still much to be learned about the best way of using viral load testing in the medical treatment of people living with HIV, and what extra information it adds to that provided by changes in the CD4 count over time. Several trials are being planned around the world to assess the role of the tests.

AVAILABILITY

At present, British clinics do not usually offer viral load testing to any of their patients. An AIDS Treatment Update survey of 15 clinics around the UK found that none is currently using the test as part of routine patient care, although several said that they hope to introduce it during 1996.

Clinics mentioned two obstacles. First, prior to the Washington conference there was very little information in how to interpret a viral load test result. Secondly, cost is a major issue. The necessary reagents are relatively expensive and each test also takes a significant amount of a skilled technician's time.

However, in April the Mortimer Market Centre in London will introduce viral load tests for selected types of patient. Clinicians will be able to obtain viral load measurements for people who are starting, resuming or changing treatment, to monitor their response, and for people who are already taking anti-HIV drugs but seem to be experiencing progression, such as a falling CD4 count or the development of symptoms.

The centre will be recording how doctors use the test and whether they find it genuinely useful. This is a service for the centre's regular patients only.

The Kobler Centre is to join with a French clinic in the Eurovir study, a formal assessment of the usefulness of viral load in guiding treatment decisions. At each clinic, 150 people who have CD4 counts below 200 and have not exhausted their anti-viral treatment options will be randomised into two groups. Half will have viral load measurements taken every two months, along with standard blood tests such as CD4 counts. The results will be available to the individuals and their doctors for use in making treatment decisions. The other group of trial participants will not have access to viral load measurements.

The aim of the study is to see whether after two years, people who knew their viral load fared any better in terms of their CD4 counts and disease progression than those who did not. The study will also assess any differences in quality of life and the cost-effectiveness of viral load testing.

REFERENCES

The AZT & 3TC study was abstract 32; the delavirdine study was abstract LB8. However, most of the viral load studies were presented at a symposium and are not summarised in the abstract book.

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