AIDS TREATMENT UPDATE, Issue 27 - March 1995
Keith Alcorn

New results from two American studies were presented at the Second National Conference on Human Retroviruses and Related Infections held in Washington at the end of January. Again, these studies only looked at the drugs' effects on surrogate markers such as CD4 counts and viral load, not on symptoms or survival. The results suggest that those who have never taken anti-retroviral drugs are likely to get the greater increases in CD4 count and decreases in viral load from the AZT/3TC combination and that combinations using a low dose of 3TC may be just as effective than combinations using a higher dose of 3TC.

TRIAL RESULTS

One trial enrolled 364 people with counts between 200 and 500 who had taken little or no AZT before ('AZT-naïve'). They were randomised to receive either AZT alone, 3TC alone or the AZT plus 3TC combination. The combination resulted in a sharp drop in viral load that remained at an average of 1 log below its baseline value even after a year. (This is equivalent to a 90% reduction in the amount of virus in the blood; for more information on log scales see the box on page 9). Combination recipients also had an average CD4 count increase of 90-100 after 40 weeks. Neither AZT alone or 3TC alone was as effective as the combination.

The other trial, however, suggested that the benefits of the combination for people who have already been on antiretroviral drugs for some time are less clear-cut. The 'AZT-experienced' trial enrolled people with CD4 counts between 100 and 300 who had taken AZT for an average of two years; they continued taking AZT and were randomly assigned to add either lower-dose 3TC (150 mg three times a day), higher-dose 3TC (300 mg three times a day) or ddC.

The combination of AZT plus 3TC caused a far bigger fall in levels of HIV in the blood (viral load) than AZT plus ddC in the first weeks, but after a year there were no significant differences between the two groups. The combination using the lower dose of 3TC to AZT was no different from that using the higher dose.

British researchers are continuing to stress that the significance of changes in viral load remains unknown. It has not been proven that a drug or drug combination that reduces viral load will also reduce the risk of HIV-related illness or death.

Side-effects

In the US studies the side-effects were similar to those seen in the earlier European studies, in which 70% of people without prior AZT experience reported no adverse effects. However, one new side-effect was reported -five out of sixteen patients receiving the drug in Toronto, Canada, reported hair loss to their trial doctor. Some patients reported severe hair loss, and one man decided to shave his head as a result. No other trial centre reported this side-effect, raising the question of whether interaction with another medication could be responsible.

Another side-effect observed with the higher dose of 3TC was hypoglycæmia (low blood sugar levels, which can cause symptoms of weakness, tremors, nervousness, breathlessness and excitement).

RESISTANCE

The American studies also produced evidence which challenges the accepted view that the development of drug-resistant strains of HIV signals a reduction in the effectiveness of the drug. Whilst resistance to 3TC developed within 12 weeks in virtually all participants, an effect on surrogate markers could still be seen beyond this period even in the group treated with 3TC alone. This illustrates that it is too simplistic simply to say that the onset of resistance means that a drug is no longer useful. Virological studies of participants in the European trial in AZT-naïve people showed that even after 24 weeks, 80% of those receiving the 3TC/AZT combination had no evidence of AZT-resistant mutations, and that the development of the specific mutation that conferred 3TC resistance also seemed to reverse or prevent AZT resistance.

UNDERSTANDING LOG SCALES

Researchers often describe reductions in viral load in response to treatment in terms of log decreases, writes Edward King. The log scale is like the percentage scale in that it describes the extent of the reduction regardless of the actual figures in question. For example, a reduction from 4 to 3 is a 25% reduction, and a reduction from 1000 to 750 is also a 25% reduction. The table below explains what log reductions mean in terms of percentage reductions, and by illustrating each reduction from a starting value of 1000.

Log scale Equivalent percentage Example

0.5 log reduction 66.6% reduction 1000 - 333 1.0 log reduction 90% reduction 1000 - 100 1.5 log reduction 96.3% reduction 1000 - 33 2.0 log reduction 99% reduction 1000 - 10 2.5 log reduction 99.96% reduction 1000 - 3.3 3.0 log reduction 99.99% reduction 1000 - 1

GLAXO BIDS FOR WELLCOME

Last month Glaxo announced its bid to buy Wellcome, writes Robin Gorna. Glaxo's experimental antiviral 3TC has shown promising results when used in combination with Wellcome's AZT. Reports on the proposed buyout have noted the neat fit of one company owning such a promising combination. Wellcome has resisted the bid and other companies have expressed interest, yet Glaxo remains the front-runner.

'Glaxo-Wellcome' would create an intriguing combination for AIDS activists. Although Wellcome's marketing department would probably lose jobs, grant-giving projects such as Positive Action are likely to stay since they are a key part of the company's PR. We should expect these to be boosted by extra resources from Glaxo's side. For HIV research Glaxo-Wellcome would be likely to bring welcome collaboration between expert researchers, without the inter-company conflicts that so often hamper progress.

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