AIDS TREATMENT UPDATE, Issue 30, June 1995
Edward King

The protease inhibitor AG1343 is active against HIV, reducing the amount of virus detectable in the blood (viral load) and boosting CD4 counts, according to the earliest results from a trial in London.

The trial at the Kobler Centre in London is the first time AG1343 has been taken by people with HIV. The drug's manufacturer, Agouron, took the unusual step of releasing information on the first person to complete the 28-day trial in order to demonstrate that the drug is active in humans. Last year a different protease inhibitor, SC52151, was abandoned after trials found no evidence of anti-HIV effects in humans, even though it did inhibit HIV in the test-tube.

The results were presented at a conference in New Mexico. After two weeks' treatment with AG1343 at a dose of 300 mg three times daily, the trial participant experienced a decline in viral load of at least 2 logs (99%). His CD4 count after nine days of treatment had increased by 116 (about 33%). Agouron says that although other trial participants may have smaller responses, the data so far suggest that some could do just as well.

Trial participants have also reported an overall feeling of well-being, and some have had improvements in HIV-related symptoms such as dermatitis, oral hairy leucoplakia and candida. The only reported side-effects have been mild episodes of lethargy, light-headedness or tightness in the chest.

No more results from the trial will be presented until a conference in Montreal in July. It is now testing higher doses of AG1343 (1200 mg a day in either two or three doses). In a recent meeting with AIDS Treatment Update, representatives of Agouron said that the results of this trial will determine whether or not they continue studies of the drug and assured us that any future trials would take place in the UK as well as overseas.

* The cause of KS?

In recent months medical journals have been full of reports confirming the detection of genetic material from a new herpes virus in Kaposi's sarcoma lesions.

As reported in AIDS Treatment Update issue 24/25, the first study detected the virus' genetic material in KS tissue samples from people with HIV as well as from HIV-negative people with KS. Recent reports have strengthened the theory that the virus is the cause of KS. It has now been found in a wide range of KS samples, but has not been detected in other tumours or in other skin samples from people with HIV. However, the possibility remains that the virus does not cause KS lesions, but simply prefers to infect KS lesion tissue.

If KS is caused by this herpes virus (on its own or in combination with other factors), drugs that inhibit herpes viruses could prove to be effective treatments for KS. The Kobler Centre and the Royal Free Hospital in London are currently pooling data in a retrospective study to see if they can detect any evidence of improvements in KS in people taking the anti-CMV drugs foscarnet and ganciclovir.

A report has already been published in a Scandinavian medical journal describing improvements in a handful of people with early KS who received foscarnet, although people with more advanced KS did not appear to benefit.

* Stavudine results

People who have been taking AZT benefit from switching to stavudine, according to new trial results.

Stavudine, also known as d4T, belongs to the same family of drugs (the nucleoside analogues) as AZT, ddI, ddC and 3TC. It was given a conditional approval for prescription in the USA last June after early results from this trial, known as 019, were released. The trial recruited people with CD4 counts between 50 and 500 who had already taken AZT for at least 6 months. Those preliminary results showed that people who switched to stavudine had an average CD4 count about 50 cells higher than people who continued taking AZT. But at that time there was no evidence that switching also had clinical benefits such as delayed disease progression or longer survival.

The final results of the trial, which enrolled 822 people, found that switching from AZT to stavudine did not result in longer survival, but did provide a three-month delay in any disease progression i.e. developing a new or recurrent AIDS-defining condition or dying. These results are consistent with trials of ddI, which also suggest that changing treatment after several months of treatment with AZT alone is beneficial.

Stavudine's commonest side-effect is peripheral neuropathy (damage to the nerves in the hands and feet causing weakness, tingling or pain), which has affected between 15% and 21% of recipients. About 1% of people suffer pancreatitis (which can be fatal) and over 40% develop increased blood levels of the enzyme amylase, which can be a sign of less serious damage to the pancreas.

Bristol-Myers Squibb, who manufacture stavudine (as well as ddI), told AIDS Treatment Update that they will be applying for the drug to be licensed in the UK as a treatment for people who have taken AZT for at least 6 months. In the meantime, the company is preparing an expanded access scheme to allow doctors to obtain the drug for use along the lines of its current US licence i.e. for people who are intolerant of or have progressed despite taking AZT, ddI and ddC. If stavudine's licence in the USA is extended so that it can be used by people who have taken AZT but have never tried ddI or ddC, these changes will also be introduced into the UK expanded access scheme.

* Viral tests and disease progression

A recently published article in the Journal of AIDS has described links between temporary high levels of HIV in the blood and a worse prognosis.

The researchers analysed regular blood samples from 28 people enrolled in three clinical trials comparing ddI with AZT. They found that most people had low levels of HIV in their blood; in some cases they were so low as to be undetectable with the test used. However, during the course of the study they identified a total of 14 samples (taken from 11 people) in which very high levels of HIV were present.

They then looked to see whether these peak levels of HIV were linked to any clinical symptoms at the same time. There did seem to be a link with an increased likelihood of rash, fever and flu-like symptoms, although these symptoms did also occur in people with low virus levels. There was also a significant link between the high HIV levels and the times when participants' CD4 counts fell rapidly.

Of the nine people who developed a AIDS-defining condition, seven had peaks in their viral levels. Only four out of the 19 people whose condition remained stable developed high peaks in their HIV levels.

The researchers point out the similarity between the symptoms associated with high levels of HIV and the symptoms some people develop soon after infection, when blood levels of HIV are also very high (see the article on page 4).

* Delta continues

The Data and Safety Monitoring Committee (DSMC) for the Delta trial of combination anti-HIV therapy met in May to review the progress of the trial. It recommended that the trial should continue as planned, adding that the next few months of follow-up information could be particularly important.

The Delta researchers originally intended to follow everybody in the trial for at least two years, but subsequently agreed that the trial should continue longer, until the end of December 1995. However, the DSMC will meet again in the early autumn when the results of the US combination therapy trial ACTG 175 will be available, and will be considered alongside the latest data from Delta.

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