TAGline/Volume 5 Issue 7
What is becoming clearer and clearer as these national and international meetings accumulate post-Vancouver is the need for new antiretroviral therapies and, especially, for new therapies with novel mechanisms of action. While the exciting potential of integrase inhibitors, nef antagonists and fusion inhibitors may be tossed around seductively at the more conceptual plenary sessions, a look at what's actually in current Phase I trials around the world betrays an ugly truth: there are virtually no novel agents in development. "Me-too" proteases, nucleosides and NNRTIs abound (see table) but are expected to convey little if any therapeutic benefit to the hundreds of thousands of HIV-infected individuals expected to fail combination antiretroviral therapy -- either for the first time or the last -- in the coming months. This is a critical short-coming little addressed at this summer's 12th World AIDS Congress in Geneva or even at last winter's Chicago Retrovirus conference. But in a feigned attempt at objectivity, TAGline checked in with AmFAR's new drug watchdog Theo Smart (who co-chaired the Geneva session on "Pre-Clinical Drug Development") and ACTG HIV-RAC co-chair Dr. Dan Kuritzkes (who gave "The Future of HIV Therapy" talk) for their takes on what we can expect from the new drug pipeline over the next 2-3 years. Afterall, they're paid to be optimistic.
The dearth of new therapies was perhaps most tangibly exemplified by the abysmal poster showings at both the Geneva and Chicago meetings this year. The Geneva poster session dedicated to "New targets/New approaches" was reportedly cancelled, and the week's two sessions for Phase I clinical trials of "new" antiretroviral agents (one oral, one print) included a total of five agents -- all merely variations on already existing therapies. "New drugs/New targets" showings in Chicago were equally bleak. Fortunately, there are a few agents in Phase I or pre-clinical development that haven't managed to make it to these international conferences, but true innovation is still mighty hard to come by. If the goal is merely to develop therapies easier to take and tolerate for future waves of HIV-infected individuals, then progress is indeed being made. If, however, the goal is to come up with additional therapeutic options for the hoards of "treatment experienced" individuals rapidly cycling through the menu of current agents, it remains unclear whether the compounds now in various stages of clinical development will be of any use.
Triangle's me-too nuke: FTC
U.S. Bioscience's me-too nuke: FddA (a.k.a. lodanosine)
If you can fluorinate 3TC, why not fluorinate ddI while you're at it? The real benefit here being that the fluorine group renders the once acid-phobic ddI acid stable. So it no longer needs all that yucky buffer and empty stomach requirements. FddA is said to get into cells better -- largely due to the fact that its activation is independent of cellular activation. But, at least in vitro, FddA appears less potent than AZT, with a mean viral load drop of 0.4 log in nuke experienced individuals.
BioChem Pharma's me-too nuke: dOTC (a.k.a. BCH 10652)
Triangle's me-too nuke: dADP
Ray Schinazi's me-too nuke: d-d4FC
Triangle's me-too non-nuke: MKC-442
Agouron's me-too non-nuke: S-1153
Upjohn's me-too non-nuke: PNU-142721
Carboxanilide analogue NNRTIs (e.g., UC-781):
Sarawak Medichem's me-too non-nuke: calanolide-A
Glaxo's me-too PI: amprenavir
Abbott's me-too PI: ABT-378
While the drug is undoubtedly potent, it is not clear that it will represent much of an option for people already resistant to other protease inhibitors. The key mutation which leads to resistance to ABT-378, at codon 84, is common in patients who have become resistant other protease inhibitors. (It is worth noting too that in none of the recombinant viruses used in late-breaker slide shows of 378's prowess was the critical 84 mutation included.)
Upjohn's me-too PI: tipranavir
Early activity data on tipranavir are not particularly impressive: Mean log plasma viral load reductions at day 11 were 1.0, 1.3 and 1.2 -- which by week 4 had been whittled away to 0.5, 1.1 and 0.9 log, respectively. By week 12, mean plasma viral load reductions were 0.6, 0.6 and 0.7 log. At the highest dose (1,500 mg TID), there was an overall 1.3 log reduction from baseline which rebounded to 0.7 log below baseline by week 12.
Part of the problem (other than the abominable study design: adding a single agent to a failing double nuke regimen -- in 1997!) was the sheer number of pills to be taken. At the highest dose, a total of 10 horse pills three times a day. Diarrhea was a big problem as well. (Maybe they shat it all out?) A new formulation with better bio-availability (and thus a lower daily pill count) is said to be in the works.
Parke-Davis' me-too PI: PD178390
Triangle's me-too PI: DMP-450
Bristol's me-too PI: BMS-232632
Japan Energy's me-too PI: JE2147
An up-coming TAGline will take a look at drug development efforts which focus on truly novel targets, but a word of caution: work to date with CCR blockers, zinc finger antagonists and integrase inhibitors has yielded mostly disappointing early results.
Just six months ago, when the whole eradication thing came crashing down on us like some rickety Times Square scaffolding, the field of HIV therapeutics (or, at least, a sizeable minority of those who had heretofore fetishized the antiviral quick fix) began to refocus its gaze away from the critical but arguably oversold antiretroviral combination therapies and toward immune-based therapies. A prescient editorial by editor Adrian Ivinson in the increasingly relevant Nature Medicine (May 1997) dared to ask whether the current obliterate-the-virus macho fixation was "likely to meet the long-term needs of the community" and called instead for a combined antiviral and immune-based approach. Well, the first hints of just such an approach have begun to trickle in -- and we can expect much more before the year is out.
Take a group of people whose plasma virus appears to have been well controlled by some sort of HAART regimen. Then tinker with their immune responses to see if you can coax back the ones that were missing (or destroyed) in the first place and enabled this insidious infection to begin taking over. While there are various proposed methods for accomplishing this, Bruce Walker's now high-profile work with long-term nonprogressors suggests that certain cellular immune responses to core HIV proteins are the ones most deserving of coaxing back.
According to Walker, this so-called "HIV-specific T help," critical to the maturation of certain specialized CD8+ cytotoxic T "killer" lymphocytes (a.k.a. CTLs), is the front line of immune attack against HIV. Its intrepid ambition, it seems, ill-serves it; and these crucial immune cells are nearly wiped out within perhaps a few days of HIV infection. Walker thinks that if we can somehow get the HIV-specific T-help back, CTLs capable of attacking and destroying HIV-infected cells will be effectively remobilized and HIV infection will be officially turned into a chronic, manageable viral infection -- like herpes or, say, genital warts. In fact, Walker as well as other research teams in Switzerland, France, Italy, Australia and the U.S. claim that they are well on their way to proving (or disproving, in the case of France's Brigitte Autran) this in newly infected individuals who are treated aggressively with antiretroviral therapy within the first 2-10 weeks of infection. (See summary of Australian Don Smith's experiment and Madame Autran's work in Lago Maggiore summary, below.)
Enter Fred Valentine and Immune Response Corp. At Geneva's poorly attended Friday late-breaker session, the 9th paper to be fired off in dizzying succession was this one which examined the use of Remune (previously known as the Salk Immunogen in its first -- or second? -- ill-fated incarnation and discarded years ago as ineffective). Valentine presented preliminary findings from a 32-week clinical trial conducted at eight research centers. Although the entire 32-weeks of treatment have been completed, only the first 20 weeks of data were said to be available for the Geneva debut.
As way of background, Valentine noted that lymphoproliferative responses ("LPRs," we'll call them) to HIV proteins are "either missing or of quite small magnitude at all stages of HIV infection." From a cohort of 101 HIV-infected individuals, Valentine showed that all but the much heralded long-term nonprogressors (LTNPs) had stimulation indexes (or "indices") to HIV env and gag proteins of <5. By contrast, LTNPs showed stimulation indices to HIV-env of 76-200 and to HIV-gag of 10 or more, "with some," Valentine cheered, "quite a lot larger." In HIV-negative individuals, Valentine explained, a stimulation index of 30-50 is "considered normal for immunogens against which a delayed-type hypersensitivity (DTH) reaction would register positive."
In the experiment, forty-three HIV-infected individuals were initially treated with the triple combination of indinavir+AZT+3TC. Four weeks after starting this regimen they were then randomized to receive either the Salk envelope-depleted vaccine or a vaccine composed of only the mineral oil adjuvant (incomplete Freund's) by intramuscular injection every three months.
After Valentine's study volunteers had ostensibly received the first two (weeks 4 and 16) of their three real or dummy immunizations, their lymphocytes were harvested and analyzed in vitro for proliferative ("LPR") responses to a panel of four antigens. The four antigens used included: 1) The Salk immunogen itself (now known as Remune or "HZ321," a Zairean clade A/clade E natural recombinant virus that accidentally lost its envelope during the Remune production process) grown in the T-cell line HuT78; 2) A core protein (p24) from the Salk immunogen itself; 3) A whole inactivated clade B virus (BaL) grown in monocyte derived macrophage cultures; and 4) A recombinant HIV-p24 protein produced in an insect cell baculovirus expression system.
In the frustratingly abbreviated slide show, we were first treated to lymphoproliferative responses to Valentine's "best responder": Subject #3. His or her stimulation index to the p24 core protein of the immunogen at Week 8 was in the 100-200 range; at Week 16, the 200-500 range; and by Week 20 around 600. "Absolutely huge responses," spracht Dr. Valentine. Responses to the whole immunogen and a different laboratory HIV strain (the clade B BaL) were also in the 200-600 range throughout the period of follow-up. What about the lymphoproliferative responses for the treatment group at large? Stimulation indices to the immunogen and its core (p24) were about 0.7 log above controls (p=0.008 and 0.03, respectively); and to the BaL strain, some 0.6 log above controls (p=0.03). "Well within the magnitude for individuals who fall into the long-term nonprogressor category," explained an exuberant Valentine. In his closing slide, Valentine concluded that "the HIV Immunogen [sic] can induce HIV-specific immune responses comparable to, in fact, and exceeding often, those seen in long-term nonprogressors."
Taken at face value, one would have thought Valentine and the Immune Response folks had stumbled onto a quick and easy recipe for a clinical cure: To four months' HAART gradually add quarterly immunizations with envelope-depleted HZ321 until of desired consistency. Let sit uncovered until trebled in volume. When knife inserted in middle comes out clean, remove HAART and allow to cool. Serve alongside a generous dollop of Dream Whip.
But cries of "Eureka!" were few and far between. With the exception of a one-day 60% up-tick in IRC's fastidiously manipulated share price and a hypo-analytical rim job in John James' AIDS Treatment News, the earth remained unshaken. Remune may have generated "astronomical" stimulation indices but precious little enthusiasm among Geneva conference goers. While some of this is a direct result of the company's penchant for sleaze and shameless self-promotion (abundantly available, it is reported, at their Thursday morning "satellite symposium"), the majority of the unethused simply observe that all Valentine really showed was that an HIV-infected individual could produce measurable immune responses to a recombinant immunogen -- something we've known (and seen over and over again with a variety of failed vaccine candidates) for years now.
What, exactly, was missing in the Remune media blitz? For starters, a broad, proliferative response to viral proteins from a panel of different primary isolates would be nice. And, of course, CTL data. Better still, what if the Immune Response bozos could show Remune capable of inducing -- or augmenting -- proliferative responses to autologous HIV; that is, the strain that an individual is infected with? Now then you might just have something! But stimulation indices to the immunogen itself? Come on, Fred, you can do better than that. "But we included a clade B heterologous strain in the antigen panel," you counter? We all know that experimental results obtained from laboratory strains painstakingly propagated in culture are notoriously misleading.
Then there's the question of the assay itself -- its sensitivity, its validation, its reproducibility, its clinical significance. As Martin Delaney and Brenda Lein, two of Project Inform's most seasoned trials analysts, observe, "We have no idea whether [the in vitro responses measured] correlate to any kind of clinical outcome. There are no data yet on whether they add, in any way, to further significant reduction in viral load. (They certainly should if Remune does what they say it does.) No information on what size changes in the assay are meaningful. No real information on the repeatability of the assay itself. No meaningful information on the durability of response. No information on how this response compares, in its clinical significance, to the original HIV specific response -- which itself almost always fails over time."
And it's curious that a product that has been shown to have a marginal (or no) effect on plasma HIV viral load (see JAIDS 1996; 11:351-64) would end up inducing a clinically significant improvement in HIV-specific cellular immunity. In a recent issue of the journal AIDS, for example, another almost as aggressively promoted prophylactic vaccine-failure-né-immunotherapeutic-vaccine, VaxSyn recombinant gp160, was reported to show clear evidence of restoration of HIV-specific T-cell immunity with no associated clinical benefit. This, again, begs the question of the clinical significance of these immune responses (see AIDS 1998; 12(2): 157-66).
Aaron Diamond's John Moore is quick to remind us that in HAART-treated individuals immune responses naturally wane because there is no longer enough antigen to maintain effector functions. This applies not only to CD4+ T cells, Moore adds, but also to B cells and CD8s. Adding some inactivated core antigens (which is all Remune is) will no doubt re-activate some immune responses that are antigen-limited in the context of HAART, Moore explains. But the re-activation of an immune response is not necessarily beneficial. "It could simply be irrelevant."
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:
To which one could add:
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.