AIDS Treatment Update, No. 44, August 1996
Edward King

- predicting the risk of disease progression in untreated people - predicting individuals' long-term response to anti-HIV treatments

Monitoring disease progression

As described in AIDS Treatment Update issue 39, a study of 181 untreated, symptom-free gay men in Pittsburgh found that their viral load predicted their risk of developing AIDS or dying. Dr John Mellors has now expanded this study by examining stored blood samples and medical records of over 1600 men who enrolled in the US Multicenter AIDS Cohort Study in the early 1980s (We.B.410).

The study confirms that the 'set-point' of individuals' viral load may provide a very accurate indicator of their risk of disease progression. The set-point is the level at which a person's viral load settles about six months after they become infected with HIV.

Mellors found that on average, people with the lowest viral load - either below 500 copies/ml, or between 500 and 3,000 - took over ten years to develop AIDS. However, for people with viral load of between 3,000 and 10,000, the average time to develop AIDS was 8.3 years; for those with 10,000 to 30,000 it was 5.5 years; and for people with the highest viral load (over 30,000 copies/ml), the average time to AIDS was only 2.8 years. Put another way, people with the highest viral load had a 13 times greater risk of developing AIDS, and an 18.5 times greater risk of death than people with the lowest viral load. There was a measurable difference in the risk of disease progression even between the two lowest viral load groups. People with viral load between 500 and 3,000 faced a 2.5 times greater risk of developing AIDS, and nearly a three times greater risk of dying, then people with viral load below 500.

Measuring viral load could identify different risks of disease progression between two symptom-free people who had the same CD4 count but different viral load. CD4 counts on their own were much less reliable predictors of disease progression, although looking at both an individual's viral load and CD4 count gave the most precise prediction. There is a strong link between viral load and the subsequent rate at which the CD4 count declines.

A separate study among 188 people with haemophilia suggested that measuring viral load between one and three years after seroconversion could help to identify people who are likely to become long-term non-progressors. Nine of the 188 still had CD4 counts over 500 and no symptoms ten years after they became infected, and of these nine, five had an early viral load below 200 copies/ml (Mo.C.323), providing further evidence that people with the very lowest viral load may have the best prognosis. But this study also confirms that other factors such as age are also important; for example, the older of two people who had the same viral load was at greater risk of disease progression.

Another study suggested that viral load may not be a useful predictor of disease progression for people with CD4 counts below 50, because the immune system is already so severely damaged (We.B.413).

The overall implication is that by having their viral load measured, symptom-free people can get a good impression of their risk of disease progression. This may help some decide whether to start anti-HIV treatment, and if so, how aggressive a treatment regimen might be needed. However, it remains unclear to what extent it is possible to alter the poor prognosis of a high viral load by using anti-HIV drugs to reduce it; researchers suspect that many people may need additional treatments to restore their immune systems.

Monitoring treatment

For people who have started treatment, several studies offered new evidence that the change in viral load after four to eight weeks provides an indication of the regimen's likely long-term effects in terms of delaying AIDS-defining illnesses and prolonging life. The new findings come from virological sub-studies of three recent trials which showed clinical benefits to drug therapy - Delta and ACTG 175 (discussed in AIDS Treatment Update issue 34) and CPCRA 007 (issue 39) all of which compared AZT monotherapy versus the combination of AZT with either ddI or ddC.

In each of these studies the regimen which showed the greatest clinical benefits in long-term follow-up also had the greatest short-term effect on viral load. Among previously untreated people in Delta, AZT plus ddI was the most effective at delaying disease progression and death, and it was this regimen that showed the greatest reduction in viral load after four weeks of treatment (Mo.B.292). Likewise, in ACTG 175 the size of the reduction in viral load after eight weeks of treatment predicted each treatment's benefits in terms of CD4 cell loss, development of AIDS and death (Mo.B.293). In CPCRA 007, AZT plus ddI had the greatest effect on viral load and the greatest clinical benefits; a one-log (10-fold) decrease in viral load after six months of treatment was associated with a 60% reduced risk of disease progression or death (Th.B.911).

The aim of treatment?

The link between low viral load and a good prognosis among untreated people, and between a reduction of viral load and an improved prognosis in those taking treatments, has led many researchers to argue that the goal of anti-HIV treatment should simply be to keep viral load as low as possible for as long as possible. As Dutch researcher Dr Joep Lange put it, "any significant amount of virus in the blood is too much".

Some therefore suggest that treatment should be considered to be sub-optimal if it doesn't rapidly reduce viral load to levels that are too low to be measured with current tests. As discussed on page 6, this approach should theoretically minimise the chance of drug-resistant HIV strains emerging. Dr Doug Richman suggested that "effective suppression of viral replication will turn patients into long-term non-progressors" (LTNPs), although this overlooks the fact that LTNPs tend also to have strong, undamaged immune systems.

After an individual's viral load has been reduced to undetectable levels, a subsequent increase in viral load might indicate that drug-resistant HIV strains had emerged. At this point, these doctors argue that the treatment should be changed, using at least two new drugs to which the virus is likely still to be susceptible, to suppress viral load to undetectable levels again. By this autumn, eight anti-HIV drugs will be approved in Europe and more are in development, reducing concerns that people will eventually 'run out' of anti-viral treatment options.

Many of the claims of the effectiveness of anti-HIV drugs presented at the conference were based on this view that the aim of treatment is to reduce viral load to below the level of detection. For example, in the studies in which recently infected people were treated with triple combinations (described on pages 2-3), the researchers are assuming that suppressing viral load to levels far below the range of the 'set-point' seen in untreated people will improve their long-term prognosis.

AIDS Treatment Update asked British clinicians whether they agree that the aim of anti-HIV therapy should be to achieve and maintain viral load below the level of detection. Professor Jonathan Weber said "I'm surprised by the concentration on undetectability. If you use a drug that produces, say, a one log drop in viral load, that will not result in undetectable viral load in people with initially high levels, but will be sufficient to push viral load below the threshold of detectability in people whose viral levels are already low. The aim of treatment is actually to make patients survive longer. If undetectable viral load is a marker of that then that's fine, but that is not yet proven. We need clear evidence of the incremental benefits of adding a third drug to two to justify the costs and the potential side-effects."

Professor Tony Pinching of St Bartholomew's Hospital said "The aim of treatment is to make sure that people do better than they would without treatments and to improve their quality and quantity of life. It is quite plausible that the means of achieving that is to suppress viral load with antiviral drugs, but how directly that will translate into clinical benefits we don't know. Something that seems theoretically plausible shouldn't be assumed to be proven until we've tested it. For patients who start treatment and have a less than adequate response in their CD4 count and viral load, there may well be a rationale for trying something additional."

Dr Mike Youle of the Kobler Centre agreed that "the aim of therapy is to drive the virus to the lowest level possible, enabling the immune system to maximise its strength, leading to fewer clinical events. So it is vital we have we have the wherewithal to regularly ascertain patients' viral load and assess resistance, to enable the prescribing of rational combinations and to guide changes in therapy".

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