AIDS TREATMENT UPDATE, Issue 29, May 1995
Edward King

A trial of a new experimental treatment begins at the Kobler Centre in London this month. The drug is called SPC-3, and consists of part of the gp120 protein that is found on the surface of HIV particles.

Before HIV can infect a human cell, it must first bind to it. A major way in which it does this is by locking its gp120 protein onto the CD4 receptor on certain cells. Gp120 fits onto CD4 like a key fitting into a lock.

Each molecule of SPC-3 contains 8 copies of an important part of gp120. The theory is that the SPC-3 molecules may attach themselves to the CD4 receptors on cells, blocking them and preventing HIV from binding to and infecting those cells. In other words, SPC-3 acts like a different key in the lock, which prevents the HIV key from being inserted.

The trial is a pilot study to test the safety and effectiveness of SPC-3. It requires a major commitment from participants since they will have to go into the clinic every day for a month to be given an intravenous infusion. Half of the participants will receive SPC-3, while the other half will be given an inactive placebo.

To be eligible for the trial you must be male and without any active infections. If you are taking antiretroviral drugs you must have been on the same dose for the last 60 days. Levels of HIV in your blood will be tested using the HIV RNA PCR test; to join the trial you must have at least 200,000 viral copies per ml of blood.

For contact details, see the side-bar on the opposite page.

* PROTEASE TRIAL DELAY

At least one of the planned UK trials of ABT-538, a promising new protease inhibitor manufactured by Abbott Laboratories, is now unlikely to go ahead owing to the speed with which the trial has recruited in the US and a delay in licensing the trial by the UK's Medicines Control Agency.

Last month AIDS Treatment Update reported that the trial would recruit twelve patients at each of two London clinics - the Kobler Centre and the Royal Free Hospital - and that the drug would be available to people who had never taken AZT. ABT-538 has produced some of the most dramatic reductions in viral load and CD4 increases yet seen with an anti-HIV drug, and the planned study was intended to investigate whether these benefits are evident when the drug is tested in a much larger group of people. It was also planned to recruit people with experience of AZT treatment to two other trials of ABT-538. There now seems to be confusion over whether these will go ahead in the UK,or whether people with HIV in London will be deprived of the option to receive this promising new drug.

AIDS Treatment Update understands that the delay is due in part to the stringency of British safety requirements for clinical trials compared with other countries. The Medicines Control Agency (MCA) is responsible for the licensing and safety of new drugs in the UK. Before an anti-HIV drug trial can begin, the MCA must grant a licence called a CTX. This is granted only when the MCA has received enough information from the manufacturer to see that the drug is safe enough to be used by people with HIV infection. In the case of ABT-538, it is understood that problems have arisen because Abbott failed to provide sufficient detailed information to reassure the MCA on the subject of possible eye problems caused by the drug. These had been spotted in animal experiments, but their significance was unknown. In the meantime the company has been able to more than fill all the available places in the trial in the United States, owing to a much more rapid system of trial approval and drug company planning.

Due to the speed with which Abbott and other drug companies are seeking to move their protease inhibitors from safety and dosage studies into larger trials, some researchers fear that people with HIV in the UK and other countries with more stringent safety requirements will face similar situations in the future. Dr Mike Youle of the Kobler Centre told AIDS Treatment Update that unless the European arms of drug companies planned well in advance, such bottlenecks would occur again and European people with HIV would lose out.

* IL-2 TRIAL DETAILS

As reported in last month's issue of AIDS Treatment Update, an American study of interleukin-2 (IL-2) showed that some recipients experienced dramatic increases in their CD4 counts. Il-2 is a cytokine, a natural signal produced by cells that stimulates the growth of CD4 cells. As reported last month, the Kobler Centre in London is to join an Australian trial of IL-2 in May or June.

To be eligible for the trial you must have a CD4 count between 200 and 500 and not have had an AIDS-defining illness other than KS. You should have been taking licensed antiviral treatments for at least 2 months prior to joining the study. Participants in the trial will continue to take their current nucleoside analogue treatment (AZT and/or ddI or ddC) and will be randomly assigned also to receive:

- placebo, or - IL-2 (given by 5 day intravenous infusion every 2 months), or - PEG-IL-2 (given by two subcutaneous injections two days apart every 2 months).

PEG-IL-2 is a form of interleukin-2 that has been altered so that it remains in the body for longer. As reported last month, IL-2 usually causes very unpleasant flu-like side-effects. For more information, contact the Kobler Centre at the address given in the side-bar of this page.

* INTRAVITREAL CIDOFOVIR

One injection of the anti-CMV drug cidofovir (also known as HPMPC) directly into the eye may be effective aganst CMV for up to two months, American researchers have reported. The drug and its delivery method are also better tolerated than the current standard of treatment, intravenous ganciclovir or foscarnet. Two studies of cidofovir injected directly into the eye have failed to show any evidence of resistance.

Dr William Freeman of the University of California said last month that "this clearly helps to control retinitis and appears to have the potential to do a better job than any other medications being given orally, intravenously or by injection. We took a completely different approach from the standard treatments, which work initially if the patient can tolerate their toxicity but are not long-lasting. When the virus acts up again doses need to be escalated or medications switched or combined, which can take hours to administer every day."

Whilst Dr Freeman is optimistic about the potential benefits of intravitreal cidofovir, further study will be needed to prove its long-term safety and effectiveness and to determine whether resistance to the drug emerges. So far the effectiveness of the drug has been studied in just seventeen patients.

The only side-effects of the drug, injected into the retina (the part of the eye which detects light and which is destroyed by CMV) were mild inflammation of the eye, and two cases of a potentially dangerous drop in the pressure of the eyeball. As with slow-release implants of ganciclovir however, eye injections provide protection only to the eye which receives the injection, whereas intravenous or oral forms of ganciclovir provide protection throughout the body. Apart from retinitis, CMV can also cause disease in the gut, lungs, brain and nerves.

A trial of cidofovir is currently recruiting at the Royal Free Hospital and the Kobler Centre in London. It is testing the effectiveness of cidofovir (injected into the body, not the eye, once a week for two weeks) as a treatment for people with CMV retinitis that has failed to respond to standard treatments or who have had to stop those drugs because of side-effects. Another trial, testing whether cidofovir can delay the progression of currently non-sight-threatening CMV retinitis, is fully enrolled and ongoing.

* QUATTRO IN LATE MAY

The Medical Research Council says that its new trial of anti-HIV drugs is now on course to start at the end of May. Organisational delays including complications in the supply of the trial drugs have put back the trial's start date by 4 months, but the problems now all seem to be resolved.

Quattro is designed to study the effect of treatment regimes containing several different anti-HIV drugs on levels of HIV in the blood, with the aim of selecting regimens for larger trials with clinical endpoints.

The trial aims to recruit participants from eleven clinics in London. A total of 90 people will be randomly assigned to one of three different arms of the trial:

- concurrent quadruple combination therapy with AZT, ddC, 3TC and loviride - cyclical therapy, using each of the four drugs on its own for an 8-week period then switching to the next in a continuous cycle - concurrent combination therapy with AZT plus 3TC

Participants will receive at least 64 weeks of treatment. The study will only be open to people with CD4 counts between 50 and 350 who have never taken anti-HIV drugs before.

* TRIAL SITES FOR THIS ISSUE

Kobler Centre Chelsea & Westminster Hospital 369 Fulham Road London SW10 9NH Tel. 0181-746 8000

Contact Sandra Davies, bleep 0388

Royal Free Hospital Pond Street London NW3 2QG Tel. 0171-794 0500

Contact Deborah Farmer, bleep 660

9505
ATU2903

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