AIDS TREATMENT UPDATE, Issue 27 - March 1995
Edward King

The Second National Conference on Human Retroviruses and Related Infections in Washington heard the results of several early studies of newer protease inhibitors.

One study looked at the effect of L-735,524, a drug by Merck, on CD4 counts and viral load among people with CD4 counts below 500. At doses of 400 or 600 mg/day, the drug boosted recipients' CD4 counts by an average of 125. A quarter of recipients had a reduction in viral load of more than 2 logs (99%). However, after about 16 weeks viral load began to rise back towards its baseline values, and at the same time strains of HIV with the mutations associated with resistance to L-735,524 began to develop. The only side-effect was increased levels of liver enzymes.

Similar promising results were reported in a study of ABT-538, a protease inhibitor made by Abbott. The drug reduced viral load and increased CD4 counts. The most effective dose appeared to be 600 mg twice daily. At the Australian trial centre, two people taking the drug experienced temporary reductions in their Kaposi's sarcoma (KS) lesions during or immediately after taking ABT-538.

* Aspirin study stops

The Community Research Initiative on AIDS in New Year has stopped its trial testing the anti-HIV effects of aspirin after participants developed shortages of red blood cells. Dr Joseph Sonnabend, medical director of CRIA, told AIDS Treatment Update that the loss of blood cells was probably caused by bleeding in the stomach, a known side-effect of regular aspirin use.

The CRIA is evaluating less toxic drugs related to aspirin with a view to continuing the study. For more information on aspirin's possible anti-HIV effects, see the article in AIDS Treatment Update issue 21/22.

* High-dose saquinavir

Several large studies have previously reported on the effects of the protease inhibitor saquinavir, alone or in combination with AZT, on recipients' CD4 counts and levels of HIV in the blood (viral load). These studies have shown that higher doses of saquinavir are more effective than lower doses, but have not tested doses above 1800 mg/day.

In Washington, US researchers reported the interim results of the first study testing higher doses of saquinavir monotherapy in a small group of people who had CD4 counts between 200 and 500. Twenty participants received 3600 mg/day of saquinavir for 24 weeks. Their CD4 counts rose sharply, peaking at about 100 above their baseline values after 2-4 weeks then slowly falling again. Blood levels of HIV initially fell by greater than 1 log (90%) then began to rise again. No side-effects were seen.

The researchers also reported on a further 18 people who had received a dose of 7200 mg/day for an average of 10 weeks. Information on HIV levels was available for only 4 participants at this dose. However, the higher doses seemed to have a greater effect on CD4 count and virus levels. The more saquinavir that was present in the blood, the greater the reduction in blood levels of HIV. These results suggest that previous trials of saquinavir used sub-optimum doses.

Some strains of HIV with the genetic mutations associated with reduced sensitivity to saquinavir developed during the study. There appeared to be a greater risk of these strains developing in people who had relatively high HIV viral load when they started treatment.

* Hydroxyurea

Hydroxyurea may be a promising drug for use in combination with anti-HIV drugs _ for more information see the article in AIDS Treatment Update issue 26. Research presented in Washington suggested that the choice of drug combination might be very important. One test-tube study found that the combination of AZT plus hydroxyurea was no more active against HIV than AZT alone. However, because of the way hydroxyurea reacts with drugs in the body, another test-tube study suggested that the combining hydroxyurea with ddI was much more likely to boost the anti-HIV effect than combinations with AZT or ddC.

* Doubts over AZT for children

American researchers have stopped the arm of a trial in which children received AZT after it became clear that they were doing worse than children treated with ddI or with the combination of AZT plus ddI. Children on AZT alone were more likely to experience disease progression, growth failure, nervous system problems or death than those given the other treatments. AZT also caused more side-effects than ddI or the combination.

These results stand in contrast to the situation in adults, in which AZT is considered to be more effective than ddI. Researchers say that the result shows that AIDS in children (in which HIV destroys the immune system before it has fully developed) may be very different from AIDS in adults (in which a fully formed immune system is damaged). Current treatment guidelines recommend the use of AZT for children, but researchers say these will now have to be reviewed.

The ddI alone and AZT plus ddI arms of the study, known as ACTG 152, will continue until late 1995.

* Loviride trial results

Dr Mike Youle of the Kobler Centre in London reported the results of an international study of the anti-HIV drug loviride (previously known as TIBOL or R89439) that included patients at his centre.

Participants in the study had to have CD4 counts between 200 and 500, six months to a year's prior use of AZT and not be diagnosed with AIDS. They were randomly assigned to take either loviride alone, AZT alone, AZT plus loviride in combination, or only a placebo for three months followed by three months of loviride alone.

After the six month trial period was completed, participants could opt to take the combination of AZT and loviride on an ongoing basis. At the time of reporting, 48 participants had taken the combination for up to 2 years. The trial assessed the effects of the treatment on participants' CD4 counts and viral load, although analysis of the latter was hindered by the accidental damage of blood samples taken at baseline.

Neither loviride alone or AZT alone had a significant effect on recipients' CD4 counts or their viral load. However, combination recipients had a significant and long-lasting increase in their CD4 count. Side-effects of diarrhoea, headaches and nausea occurred in almost everyone, but these had usually stopped after the first 2 months. No strains of HIV with the genetic mutations associated with reduced sensitivity to loviride developed even among those taking the combination for up to two years.

Dr Youle told AIDS Treatment Update that future research into loviride will test doses three or four times higher than those used in this study, and will also investigate the effects of the triple combination of AZT, 3TC and loviride. For a full report on the triple combination trial, see the article "3TC trial begins" in issue 26.

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