A View from Afar
Conference Circuit Ingénu and Self-Appointed Apothecaire Dispenses Bitter Tonic at Congress' Close
Word of 'a serious malaise'
As part of the "rapporteur" element of this year's world AIDS congress, 12 minute summaries of each of the four tracks (A=Basic Science; B=Clinical Science and Care; C=Epidemiology, Prevention and Public Health; D=Social and Behavioral Sciences) were prepared each morning at 8:00 a.m. by teams of volunteers led by a recognized authority in each of the four disciplines. At the official Closing Ceremony on Friday morning (July 3rd), each of the four track "team captains" presented a 30-minute review of the entire week's presentations for his or her respective track. What follows is a transcript of Richard Horton's highlights of the clinical science (B) track -- followed by a foray into his impressions of the meeting as a whole. Horton's remarks were met by choked throats as well as cheers which culminated in an extended standing ovation. Those who skipped out early or chose Friday as the day to sleep in missed a legendary wrap-up.
It seems a longtime since the data from Concorde were first published, to general disbelief and anger, I recall, as well as newspaper headlines such as this one [slide of newspaper clipping: "Setback for AIDS Research as AZT Fails in Tests"]. 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 than 50 copies/mL, 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 enormously since Vancouver 2 year ago. 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 this 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 copies/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 1,028 possible 4-drug combinations. Not all of these regimens can be tested, and we heard sharp disagreement this week about how to proceed. 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 generalizable are results from trials; and how do we get the right balance -- and this has not been discussed enough at this meeting -- between the ethics and enthusiasm (of some people) for doing drug trials -- for perhaps dubious motives.
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 -- hopefully -- for an effective protease-inhibitor-sparing regimen. It seems to me that this is one finding likely to change clinical practice most quickly.
But ... there was bad news as well. Despite the fact that we have more choice (which is good), toxicity, resistance, adherence, and cost all remain issues which have yet to be dealt with properly. They've combined to produce a really quite striking turn-around, I think, amongst opinion leaders on treatment, to me anyway. The "hit hard, hit early" approach that has dominated all discussion during the past 2 years has now been massively tempered. There is now "caution" -- as if we've been cautious for many years. Caution is emphasized 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. That perhaps should be acknowledged a little more because there are lessons to learn from this. 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 that we are using.
Now this is a slide that wasn't shown this week and it says: "Highly active antiretroviral therapy including a protease inhibitor will make HIV infection a chronic manageable disease just like ..." and there are a list of chronic manageable disease and the last one is ... diabetes. Well, how very true -- in a very sad irony. Exactly like diabetes, in fact, as we have learned this morning from Andrew Carr. The lipodystrophy syndrome -- peripheral fat wasting, abnormal fat accumulation, hyperlipidemia, diabetes mellitus. The physical effects are striking and disturbing [slides of each]. Now the good news is that there is a potential mechanism for understanding what's going on here. All of which raises the absolutely urgent question of how drug regulatory authorities exert power -- which is presently weakness -- perhaps by issuing only a provisional license to a manufacturer to demand that drug companies collect long-term safety data on products that go through accelerated approval procedures. [applause] Certainly, that lesson needs to be learned for efavirenz and other new drugs.
What are the future issues, for developed world research? 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 (possibly hydroxyurea)?
- 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/mL on triple therapy).
- What new drug targets can we discover?
- Who will provide liquid formulations, so desperately needed for children?
What all these results show -- greater choice in treatment, more complications, the need to individualize treatment -- is that, as Julio Montaner said, "There is too much at stake to leave it to those who are not properly qualified." We have to work harder to properly train all health-care workers in the skills necessary for appropriate care.
Now let me move on to the prospects for the developing world where 800 million people lack access to health services. And 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: it's explosive in Cambodia and Southern Africa, where 20% of antenatal clinic attendees are HIV positive. It's masked in countries such as Rwanda, where there is a high incidence in poorly monitored populations, such as those in rural communities. And it's emerging with pockets of high incidence in particular groups, such as injection 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 and presented this week that the worldwide cost of triple antiretroviral therapy would be 36.5 billion U.S. dollars, of which two-thirds would need to be spent in Africa. The prospects for any accepted Western standard-of-care being introduced into the developing world looks depressingly bleak. Children, I think, face an especially depressing outlook. By 2010, AIDS may increase infant morality by 75%; the under-5 mortality by perhaps by 100%. And although the Thai short course regimen, which we've already heard about, offers the hope of a practicable treatment solution to prevent perinatal infection, breast feeding remains an unresolved (and under-discussed) issue. Breastfed babies have an increased risk of becoming infected with HIV -- in absolute numbers, perhaps around 270,000 each year. But breast-feeding also protects against diarrhea and respiratory tract infections, which are diseases that are far more common in these parts of the world than HIV.
Still, I don't want to be too gloomy; it's easy to be gloomy. There were several examples of successful collaborations, for example, in the conduct of clinical trials. In Thailand, the HIV-NAT program 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 multicenter protocol can work.
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 tantalizing 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.
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. It makes me a mere beginner, I think, at these sort of 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. And 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. But I've gotta tell you I'm going to leave Geneva with an overall sense of disappointment. Not disappointment about the slackening pace of research. Far from it. There's been a remarkable explosion of new research that's been presented at this meeting in Geneva. But rather a disappointment over something that I think may be a little more serious. A malaise, perhaps, amongst the total AIDS community: among scientists, physicians -- and activists.
Now this conference was about "bridging the gap." So why was it, 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, the halls began to bleed delegates [thunderous applause] 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 nothing less than shameful.
It is always an easy target to compare negatively government spending on military budgets with that money spent on AIDS. We can all, myself included, be dutifully shocked and horrified. Our rage doesn't cost us a cent. But if you walk out of a room when your own colleagues have travelled long distances in sometimes difficult circumstances to share their experiences with you, why should any government bother to 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; it remains unanswered. This week has also shown that the conference needs to renegotiate its contract with the pharmaceutical industry. I am only too well aware that a huge gathering such as this could not possibly take place without industry support. I also know, and do not dismiss, the fact that 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 was it -- why was it -- that I could find barely a mention in the plethora of satellite symposia and exhibition stands, about how industry plans to bridge the gap? [more cheers, applause and cat calls] In our rightly correct emphasis on partnership and collaboration between different sectors of the AIDS community -- between investigators and activists, between doctors and other health-care professionals, scientists and PWAs -- why is it that industry is so often exempted? It's almost as if -- it's almost as if -- we've become so dependent on their hospitality -- and we have, let's face it -- that we cannot bear to bite the hand that feeds us. And that failure seems to me to be a betrayal that gets bigger with the passing of each conference.
This meeting has done 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, Southeast Asia, and other parts of the developing world. Why is it that 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've 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 to those in the North. But any principle like that will be completely pointless if we cannot practice the oldest and still, I believe, the most important skill of any good doctor: that of first listening with humility.