AIDS TREATMENT UPDATE Issue 26 - Feburary 1995
Robin Gorna

Glaxo, manufacturers of 3TC, refer to the new trial as 'The Clinical Endpoints Study' because it looks at the effects of the drugs on the clinical course of the disease, not just laboratory test results. The study, code-name NUCB3007, is also hoping to establish whether the effect of a treatment on viral load can truly predict its likely effect in terms of delaying illness or death. If so, this would have important implications for the future development of anti-HIV drugs.

* Validating viral load

It is well known that, on average, as HIV disease progresses, the CD4 cell count decreases and HIV viral load increases. However, it is unclear whether changes in CD4 count or viral load during antiviral treatment can be used to predict changes in the longer term course of disease. NUCB3007 will compare the extent to which the compounds affect levels of HIV in the blood with the effects they have on the clinical course of disease. If there is a clear link, trials may be able to assess the effectiveness of a drug by its effect on viral load rather than having to wait until participants develop symptoms or die.

The need to validate surrogate markers became a major concern following the results of the Concorde study comparing immediate with deferred use of AZT (see AIDS Treatment Update issue 6). Concorde found that the group who received AZT early had, on average, a persistently higher CD4 count than those who received it later, but that despite this difference early AZT did not delay disease progression compared with later use. The implication of Concorde was that trials must evaluate the effects of treatments on clinical endpoints. This, however, is an approach that people with HIV and treatment activists had traditionally rejected as unreasonable and too lengthy. The search is therefore on for more reliable surrogate markers, and viral load is currently one of the most hopeful candidates.

* Defining disease progression

NUCB3007 has developed a novel staging system to measure disease progression. In many clinical endpoint studies, developing any of the AIDS-defining conditions is counted as disease progression, even in someone who already has AIDS. This means that people who develop, say, candida in the oesophagus are counted as 'progressors' along with people who develop MAI, despite the fact that the latter is a far more serious condition that only occurs when the immune system has suffered much greater damage. At entry to the trial people are assessed as being in one of three groups _ asymptomatic, 'mild' AIDS or 'severe' AIDS. The idea is that if someone who has had PCP ('mild' AIDS) progresses to MAI ('severe' AIDS), this counts as an endpoint, while if they develop candida ('mild' AIDS) this does not count as an endpoint. It is hoped that by making this distinction the trial will measure more accurately the effects of therapy.

The innovatory design for NUCB3007 has been developed in consultation with community representatives from several countries. The use of 'current treatment' as the comparison arm is broadly in line with suggestions for trial designs made by the Treatment Action Group (TAG) in New York. However, it is understood that the American Food and Drug Administration (FDA) considers the trial too 'avant garde' and is blocking American centres from participating.

* Trial design

The prime goal of NUCB3007 is to show whether adding 3TC, or both 3TC and a second anti-HIV drug, loviride, to currently licensed treatments has a greater effect than those current treatments alone. The trial has three arms: - current treatment only - current treatment + 3TC - current treatment + 3TC + loviride.

This international trial will last for 12 months and will recruit 1200 men and women with CD4 counts between 25 and 250. As half the participants will be allocated to the second arm, only 25% of participants will receive current treatment alone.

The trial is likely to attract people because no-one is asked to stop their current treatment. Although the trial would be simpler using just AZT as the current treatment, NUCB3007 allows participants to continue with whatever antiviral regime, including combinations, that they are using, so long as their regime includes AZT.

If there is toxicity, resistance or a significant decline in health (which would include a sustained drop in CD4 count to 50% of its value on entering the study), the current treatment can be changed. Participants who progress to a clinical endpoint will be allowed to receive open label treatment with 3TC and loviride on top of their current antivirals. Everyone participating in the trial (except for those who withdraw from the study at their own request) will be offered continued access to the study drugs at the end of the trial.

In Britain, the following centres will be recruiting participants:

Kobler Centre Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9HT Tel. 0181-846 6135 Contact: Dr Mike Youle

Leeds General Infirmary Dept of GU Medicine, Great George Street, Leeds LS1 3EX Tel. 0113-292 3279 Contact: Kath Short or Gerald Booth

Mortimer Market Centre Mortimer Market, off Capper Street, London WC1E 6AU Tel. 0171-380 9660 Contact: Dr Ian Williams

Royal Free Hospital Pond Street, Hampstead, London NW3 2QG Tel. 0171-794 0500 Contact: Dr Margaret Johnson, Deborah Farmer (bleep 660), David Stobbs (bleep 477)

St Mary's Hospital Jefferis Wing, Praed Street, London W2 1NY Tel. 0171-725 6619/6620 Contact: Vania Gay

* Expanded access to 3TC

Very few people in the UK have had access to 3TC. The seven people who participated in the original trials have been offered the drug since the trials ended, but there have been no expanded access schemes for other people with HIV. By contrast, in the USA and all other European countries a protocol for expanded access has been in place for the past year. Although this protocol, code-name NUCB3004, was rejected a year ago, it is expected that in the next few weeks it will be approved by the Medicines Control Agency (MCA), the UK body responsible for allowing studies of unlicensed drugs.

The expanded access scheme enables some people who are not eligible for controlled trials of 3TC to obtain the drug. Doctors can obtain 3TC through the expanded access scheme for treating people with a CD4 count below 300 who no longer benefit from AZT, ddI or ddC because of side-effects or disease progression. Children under three are excluded, as are pregnant women and people with chronic liver disease due to hepatitis B or C. As the drug's effects are still not fully known, access is restricted and people receiving 3TC will be monitored at least every three months. However, the data gathered are less detailed than in a randomised double-blind trial.

The requirement that people cannot take the licensed antiviral therapies is fundamental to the expanded access scheme, but also problematic. As monotherapy, 3TC is believed to have limited benefit. All of the data so far suggests that greater benefit is achieved when 3TC is taken with AZT, even for people who have developed resistance to AZT. It is understood that the majority of people receiving 3TC through the expanded access scheme in other countries are also using AZT, often covertly. Glaxo told AIDS Treatment Update that although people in the expanded access scheme are "not encouraged" to use AZT, it is not disallowed. People who have stopped AZT because of lack of benefit may feel justified in resuming AZT in combination with 3TC on the basis of the promising surrogate marker data.

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