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CLINICAL SCIENCE AND CARE - TRACK B
Closing Comments 29 June - 3 July, 1998

• I want to spend my impossibly brief 15 minutes reviewing 3 aspects of this meeting -
• Developments in clinical science and care in the developed world.
• The same, but in the developing world
• A few personal impressions from someone who is not quite yet a dinosaur of the AIDS Conference circuit.

"Setback for AIDS research as AZT drug fails in tests."
It seems a long time since the data from Concorde were first published, to general disbelief and anger, I recall, as well as newspaper headlines such as this one. But since then - only a matter of a few years, in fact - we have moved through a phase of dual combination antiretroviral regimens, first described in the Delta study, and on into the triple-drug era. Antiretroviral therapy (ART) is now viral-load driven, aiming for suppression to below 50 HIV-RNA copies/mL within a matter of weeks. Anything greater, and ongoing replication is taking place, allowing resistance mutations to evolve. The good news at this Conference is that we now seem clear and agreed about our goal - maximum suppression of viral load.

But the issues have shifted. Our notions of eradication have been modified; more sensitive viral-load assays have been developed; and there are now more options in HIV therapy. Attempts to eradicate virus have so far been thwarted by the existence of HIV in reservoirs of latently infected resting memory cells. But David Ho reported data this week showing that the pool is vulnerable to attack with ART, declining over a 35-month period with a half-life of 6 months. More sensitive viral-load assays have shown us how important it is to suppress viral replication - levels below 50 c/mL are associated with more durable responses. Currently, we have 11 approved antiretroviral compounds. Soon we will have 15, once efavirenz, amprenavir, adefovir, and abacavir are licensed - that means 204 possible triple combinations and 1028 4-drug combinations. Not all of these regimens can be tested and we heard sharp disagreement this week about how to proceed. One person argued, and I will not embarrass him by repeating his name, that there is no need for a clinical trial end-point study for every regimen. Another commentator believed that practice must be driven by data, not intuition. Now there is a revolutionary idea.

There are many trial issues that still remain to be settled: which end-points should be selected; which method of analysis should be adopted; how can we best mask studies; what is the answer to the vexed question of standard of care in developed and developing countries; how generalisable are results from trials; and how do we get the right balance between the ethics and enthusiasm of doing drug trials, a balance that has not always been achieved in the short history of AIDS research. Data on efavirenz were especially intriguing. We heard that a 24-week phase III study showed that efavirenz plus indinavir was equivalent to the new standard 3-drug regimen of indinavir, AZT, and 3TC. Efavirenz, AZT, and 3TC were better than either of these 2 combinations alone, allowing for an effective protease-inhibitor-sparing regimen. It seemed to me that this result is the one likely to change clinical practice most quickly. But there was bad news as well. Despite the wider choice, a good thing for sure, toxicity, resistance, adherence, and cost have all combined to produce a quite striking about turn in the views of opinion leaders on treatment - the "hit hard, hit early" approach has been tempered.

Now caution is emphasised with the option of deferring therapy if a person is asymptomatic with a low risk of progression. How very different from a few years ago. One reason for this dramatic pull-back from the aggressive positions of the past is our understanding of the serious adverse effects of the drugs we are using. Here is a slide that wasn't shown this week: "Highly active antiretroviral therapy including a protease inhibitor will make HIV infection a chronic manageable disease just like... diabetes". Unattributed, but said, nevertheless, in Vancouver. Well, yes, exactly like diabetes in fact, as we have learned this morning from Andrew Carr. The lipodystrophy syndrome - peripheral fat wasting, abnormal fat accumulation, hyperlipidaemia, diabetes - produces physical effects that are striking and disturbing, even though we do now have a potential mechanism for understanding how the syndrome develops. All of which raises the urgent question of how drug regulatory authorities exert power, which is currently weakness, to demand that drug companies collect long-term safety data - perhaps by issuing only a provisional licence - on products that go through accelerated approval. Certainly, that lesson needs to be learned for efavirenz and other new drugs. Expanded choice has also been balanced by an appreciation of the importance of treatment adherence.

Whatever the reasons for non-adherence, we all have to work harder - and it takes time, there are no short cuts - to individualise treatment to the person's unique circumstances. A randomised trial of hospital pharmacist intervention, reported this week, showed that there are ways to help adherence, ways which significantly reduce viral load. What are the future issues? The key concerns are these,

• What is the optimal timing for initiation of therapy?
• What is the target level for pVL suppression?
• What is the optimal antiviral potency?
• What is a definition of drug failure?
• How should we handle drug sequencing/recycling?
• What about adjuvant therapies?
• What will be the results of prospective clinical testing for resistance?
• What about access/cost?

To which one could add -

• Where are the trials in advanced disease?
• How do we improve palliative care? And I am thinking here of the fantastic talk we heard yesterday from Jim Oleske.
• Is immune reconstitution possible? (It is already taking place since OI prophylaxis is often stopped once CD4 counts rise to 200-400/ L on triple therapy).
• What new drug targets can we discover?
• Who will provide liquid formulations, so desperately needed for children?

What these results show - greater choice in treatment, more complications, the need to individualise treatment - is that, as Julio Montaner said, too much is at stake to leave it to those who are not properly qualified. We need to make sure that we have properly trained teams of health-care workers to administer the best care possible.

Second, what are the prospects for the developing world, where 800 million people lack access to health services. Here, as Charles Carpenter told us on Thursday, "the treatment gap is not even close to being bridged."

• Part of the problem is that the epidemic is just simply out of control:
• Explosive in Cambodia and Southern Africa, where 20% of antenatal clinic attendees are HIV positive.
• Masked in countries such as Rwanda, where there is a high incidence in poorly monitored populations, such as rural communities.
• Emerging, with pockets of high incidence, as among injecting drug users in the Ukraine.

This epidemiology makes the clinical science, let alone the clinical care, astonishing difficult. And the costs remain crippling. Robert Hogg calculated that the worldwide cost of triple antiretroviral therapy would be US $36.5 billion, of which two-thirds would have to be spent in Africa. The prospects for accepted western standards of care reaching developing nations look depressingly bleak. Children face an especially poor outlook. By 2010, AIDS may increase infant morality by 75% and under-5 mortality by over 100% in some places. Although the Thai short-term regimen offers hope of a practicable treatment to prevent perinatal infection, breast feeding remains an unresolved issue. Breastfed babies have a greater risk of becoming infected with HIV - as many as 270 000 each year - but breast feeding also protects against diarrhoea and respiratory tract infection, diseases that are far more common than HIV. Still, I don't want to be too gloomy. There were several examples of successful collaborations to conduct clinical trials. In Thailand, the HIV-NAT programme links with Australia and the Netherlands. Trials are run according to locally relevant protocols and generate the enthusiastic commitment of local health-care workers, and, as a consequence, achieve rapid and impressive recruitment. Also in Thailand, trials comparing dual combination regimens have been completed, again showing that a multicentre protocol can work. Wafaie Fawzi and colleagues reported some especially exciting findings in Tanzania. They found - in a randomised trial of over 1000 pregnant HIV-positive women - that women receiving multivitamins had significantly fewer fetal deaths and significantly higher CD4 counts. Multivitamins also reduced the risk of low birthweight and preterm delivery. A further driving force behind HIV in developing countries is the high prevalence of STDs. I was disappointed that there were not more reports this week on the interaction of STDs and HIV in developing regions of the world.

And then there is TB - the leading cause of death among people with HIV. It was tantalising and hugely encouraging to read the report that cotrimoxazole can significantly reduce by almost half the rate of death among HIV-infected people with TB in Africa.

A quick thought.

The Global Burden of Disease study is a World Bank-WHO funded project to model how the world's health is going to evolve up to 2020. I want to show 2 simple summary slides. One reporting on death and the other on a measure of disability - the disability-adjusted life year or DALY.

First, rankings for death. 1990: HIV is not there at all. By 2020, HIV has now risen to the number 9 position. Note that diarrhoeal diseases and measles have fallen out of this top 10.

Second, rankings for DALYs. 1990: HIV is not there. By 2020, HIV is at number 10. Note that diarrhoeal diseases have fallen from number 2 to number 9.

These models are just that - only models. But they do two things. They show how HIV is going to accelerate in importance in the world's overall burden of disease during the next 20 years. And they also place HIV in the context of other diseases, especially cardiovascular disease - another developing world epidemic - which will all have to compete for cash from the same limited pool of money.

Finally, perhaps I can turn to the Conference itself. These thoughts are not part of Track B. This is only the third international AIDS meeting that I have attended. I'm a mere beginner, I know, at these events. At the opening press Conference, Peter Piot, Executive Director of UNAIDS, spoke of the "total collective failure" that had led to 10 million more people acquiring HIV since the Vancouver meeting in 1996. That same day, Ruth Dreifuss, the Swiss Minister of Health, called for "strong political leadership and support" to combat AIDS. And Mark Harrington, Treatment Action Group's Senior Policy Director, said that "only political pressure and science can bring us any further". Perhaps I could add to those two important truths - public support and public pressure. So essential to maintain and encourage further investment into research and our commitment to the developing world. Their statements should act as rousing calls to all of us to go away and renew our own personal commitments to tackle AIDS. Bernard Hirschel and Robin Gorna, our Conference chairs, have organised a superb meeting and they deserve our thanks - as well as a well-earned vacation.

But I shall leave Geneva with an overall sense of disappointment. Not disappointment about a slackening pace of research. Far from it. There has been nothing less than an explosion of new research in Geneva this week. But a disappointment over something more serious. A malaise, perhaps, amongst the AIDS community itself - among scientists, physicians, even activists.

This Conference was about "bridging the gap". Why was it, then, that every day this week, whenever a speaker from a developing world country rose to talk about an issue central to "bridging the gap", seats emptied and the hall began to bleed delegates through the aisles and out into the corridors of the Conference centre. I watched this happen at least 6 times to speakers from Africa, India, and Thailand.

It was shameful.

It is always an easy target to compare negatively government spending on military budgets with that money spent on AIDS. We can all be dutifully shocked and horrified. Our rage doesn't cost a cent. But if you walk out of the room when your own colleagues have travelled long distances in sometimes difficult circumstances to share their experiences with you, why should any government listen if you don't?

On Monday, Mercy Maklamena asked us what it is about medical education and training that produces doctors of such limited vision. That question hangs over this closing ceremony today. This week has also shown that the Conference needs to renegotiate its contract with the pharmaceutical industry. I am well aware that a huge gathering such as this could not possibly take place without industry support. I also know, having heard and read the testimonies of many HIV-positive men and women, that drugs have made an incredible difference to their lives. But in a Conference aimed at "bridging the gap", why could I find barely a mention, in the plethora of satellite symposia and exhibition stands, about how industry plans to bridge that gap?

In our rightly correct emphasis on partnership and collaboration between different sectors of the AIDS community - investigators and activists, doctors and other health-care professionals, scientists and PWAs - why is industry so often exempted? It is almost as if we have all become so dependent on their hospitality - and, lets face it, we have - that we cannot bear to bite the hand that feeds us.

And that failure seems to me a betrayal that gets bigger with the passing of each Conference.

This meeting does a great deal to focus the world's attention on one of the most devastating epidemics to affect the economically poorest amongst us.

It seems to me that we need to send another signal to mark the importance we all attach to AIDS and the wider health problems of people living in Africa, S-E Asia, and other parts of the developing world. Why do we have to wait 2 years before the next meeting? Is AIDS not a sufficient crisis to restore its only world Conference to annual status? Doubling the frequency of this meeting would help to extinguish the threat of complacency amongst public and politicians alike.

And so onto Durban.

This week we have had the Geneva principle - giving an equal voice to those in science and those in the wider AIDS community. Perhaps the Durban principle might be to give an equal voice to those in the South as well as the North. But that principle will be pointless if we cannot practice the oldest and still, I believe, the most important skill of a good doctor - that of first listening with humility.

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