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TAGline/Volume 5 Issue 7
Double Summer (Geneva) Issue

August/September 1998


  1. Geneva "New Agents" Sessions Betray Dearth of Interest in Imaginative (or Costly) Drug Development
  2. One Part Aged Innovation, Two Parts Hubris: Is Remune Merely Reheated '93 Berlin Fare?
  3. Whither Eradication? 1996's Naïve Assumptions
  4. Conference Circuit Ingénu and Self-Appointed Apothecaire Dispenses Bitter Tonic at Congress' Close
  5. Highlights from the Resistance Workshop

"Me-too"s Rule

Geneva "New Agents" Sessions Betray Dearth of Interest in Imaginative (or Costly) Drug Development

Everything new is old again

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
FTC is a fluoronated version of 3TC, with somewhat greater potency than 3TC -- at least in the lab -- and the very same resistance profile. Yes, M184V brings it to its knees. The hook here is that it can be dosed once a day. (But then 3TC is already being dosed that way in Europe...) Results from a Phase I/II study were presented at the February Chicago meeting -- and again in Geneva -- with a mean plasma viral load reduction of some 2.0 logs at the higher (200 mg QD) dose.

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)
Member of a new class of "hetero-substituted" nucleoside analogues. Reported to have activity against clinical isolates resistant to 3TC and AZT. Resistance is said to be "slow to develop": no change in the IC50 and no evidence of RT mutations after 12 serial passages in the MT-4 cell line. Studies in animals suggest a good safety profile. Moving into Phase I/II.

Triangle's me-too nuke: dADP
Guanosine analogue. Yet to enter human study. Said to be a super nuke, "like abacavir." (Great.) Also has activity against hepatitis B. In the SCID-Hu mouse model, dADP is less potent than FTC. Little or no cytotoxicity thus far.

Ray Schinazi's me-too nuke: d-d4FC
A cytosine nucleoside (like 3TC and ddC) claimed to be active against multi-nucleoside resistant (MNR) HIV, at least in cell culture. The active metabolite is reported to be a more active chain terminator than that of 3TC, but it is reported to be less potent than FTC in the SCID-Hu mouse. Half life in monkeys of about 4 hours. No human data yet.

Triangle's me-too non-nuke: MKC-442
The nucleus of this non-nuke is actually a nucleoside analogue (which resembles a pyrimidine). Currently in Phase II/III, making it the RTI furthest along in development. One to one-and-a-half log drop in plasma viral load in a 15-day Phase I/II study. So far, it's being dosed twice daily. Unfortunately, it reportedly only takes one mutation -- the ubiquitous K103N -- to knock it out. That imposes serious limitations.

Agouron's me-too non-nuke: S-1153
Agouron recently acquired the rights to this NNRTI claimed to exhibit a "10-fold greater in vitro potency than either nevirapine or delavirdine." Phase I results were presented in Chicago and again in Geneva. In a subset of 11 study volunteers with baseline viral loads > 10,000 copies/mL, the mean viral load reduction with S-1153 was 1.74 logs. Said to be active against the K103N mutant and to require a minimum of 2-3 mutations in order to develop significant resistance. Good bio-availability with or without food. BID dosing possibilities.

Upjohn's me-too non-nuke: PNU-142721
A thiopyrimidine. Low protein binding, according to Dan Kuritzkes. BID or QD dosing. Said to be active against delavirdine resistant HIV.

Carboxanilide analogue NNRTIs (e.g., UC-781):
No Phase I data to be had. Upside? In general, they tend to have a very long half-life. UC-781 inhibits RT-dependent pyrophosphorolysis and purportedly restores the chain terminating activity of AZT against AZT-resistant virus (as does the A114S foscarnet resistance mutation). Downside? They currently require intravenous administration.

Sarawak Medichem's me-too non-nuke: calanolide-A
Calanolide-A is reported to have been isolated from the Malaysian rain forest and subsequently synthesized for clinical development with a plasma half-life of some 20 hours. To date, only Phase I PK and safety data are available.

Glaxo's me-too PI: amprenavir
Next in line for FDA licensure after efavirenz and abacavir. Many protease resistant folks (and their physicians) are betting on it for at least a temporary viral load reprieve. Fact or folly? While mutations at codons 46, 47 and 50 -- with 50 predominating -- are first to appear, subsequent cross-resistance mutations at the more familiar codons 82, 84, 10 and 36 have been reported in a significant number of patients failing amprenavir therapy in Phase II trials. Additional mutations were also detected at the p7/p1 and p1/p6 site of gag in many of the patients. So broad class resistance still seems to be the rule of thumb here.

Abbott's me-too PI: ABT-378
Why do they call these agents "second generation," anyway? Ostensibly because, as Dan Kuritzkes put it in his Geneva talk, they've been "developed to have potency against [protease] resistant virus." And, in fact, Abbott's 378 does appear to have an IC50 about 10-fold lower than its predecessor -- whether against wild-type HIV or protease resistant HIV. Like Upjohn's tipranavir, 378 is poorly absorbed and will likely require co-administration with low-dose ritonavir.

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
The first of a new class of non-peptidic protease inhibitors, tipranavir is said to be effective against ritonavir and indinavir resistant HIV. This is due to its chemical structure which, according to Smart, seems to be a bit more flexible than the peptide-based inhibitors.

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
Another non-peptidic protease inhibitor said to exhibit activity against resistant HIV. PD178390 is also unique in that it is not metabolized through the cytochrome P450 system; that should cut down on drug-drug interactions, but will also disqualify it for potentiation by P450 inhibiting agents such as ritonavir. While Theo finds this "the most promising protease inhibitor in development," cross-resistance and protein binding may turn out to plague this hot-shot wanna-be just as they have plagued past early protease-inhibiting favorites. Mutations at amino acids 10 and 36 increased the IC50 of the drug at least 4-fold, and when human sera or alpha acid glycoprotein was added to the mix, the IC50 for PD178390 increased an additional 2 to 4-fold. The drug's half life in mice is a mere 2.2 hours.

Triangle's me-too PI: DMP-450
The third non-peptidic protease inhibitor (it's a cyclic urea compound) is also said to have different side effects from the other PIs since it binds differently to the enzyme -- and is metabolized differently. Also the second PI in development to steer clear of the cytochrome P450 system. Apparently simple and inexpensive to manufacture. And since it is not highly plasma protein bound, it should be active at fairly low doses. Its water solubility lends itself well to a pediatric formulation. Appears to share cross-resistance with ritonavir and indinavir, so again it is unclear whether it will represent much of an option for protease resistant folks.

Bristol's me-too PI: BMS-232632
An azapeptidic protease inhibitor. As is the case with DMP-450, the Phase I study is expected to be completed by year-end.

Japan Energy's me-too PI: JE2147
An allophenylnostatine protease inhibitor, also recently licensed to Agouron. Like DMP-450, it is not highly protein bound and therefore expected to be active at lower doses. Said to be active against protease resistant virus, but the ubiquitous 82 mutation (along with 10 and 47) pop up after in vitro serial passage. Plasma half-life of only 1.5 hours.

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.

Copy cat agents profiled within:
Nuke RTIs Non-nuke RTIs Protease inhibitors
JE-2147 (a.k.a. KNI-764)

Recipe for a Cure

One Part Aged Innovation, Two Parts Hubris: Is Remune Merely Reheated '93 Berlin Fare?

Memories of mock apple pie

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."

Whither Eradication?
Nineteen ninety-six's naïve assumptions:

  • Drugs are shutting off virus replication 100%. Nope. More sensitive tests now regularly produce evidence of low level on-going viral replication.

  • Infected cells turnover and die. Guess again. Most researchers show no decay of latently infected CD4+ memory T cells (the best characterized source of chronic infection to date), while Ho's new estimate of the half life of these cells figures in at 6 months. This translates into an "eradication" time table of some 15-20 years.

  • No "privileged sites" or "third" (fourth or fifth) compartment exists. Oops! There now appear to be reservoirs of virus -- whether anatomical or pharmacologic -- that the current class of agents simply cannot reach.

  • 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.  

    Highlights from the Resistance Workshop

  • Like last year's discovery of the gag cleavage site mutation for the protease inhibitors (which this year investigators from Virco reported to be found in up to 55% protease resistant clinical isolates), this year saw several papers reporting a 2-3 amino acid insertion between codons 68 and 70 of the RT gene which was associated with multi-nucleoside resistant virus. An Amsterdam group found the 2 amino acid insert conferred phenotypic resistance to 3TC, d4T, ddI and ddC without displaying the corresponding associated mutations. "These viruses might be insensitive to the whole class of nucleoside RT inhibitors which can have major implications for subsequent antiretroviral treatment." And they go on: "Besides, resistance assays focussing only on the currently known resistance associated mutations miss this new resistance profile and will therefore give the incorrect impression that these viruses are still sensitive to nucleoside RT inhibitors."

  • Investigators from Glaxo Wellcome (of all people!) showed that individuals with multiple mutations to several NRTIs have an attenuated -- or no -- response to abacavir.

  • So-called "baseline polymorphisms" in the protease gene are increasingly reported among protease naïve individuals. In a French study, pre-existing mutations were observed in 8/11 patients, with a mean number of five mutations per patient. In a separate paper (Statens Serum Institut, Denmark), the L63P baseline mutation was associated with an inferior virologic response to therapy (p=0.08).

  • A quad mutant to ritonavir (36I-54V-71V-82T) cloned from a clinical isolate was shown to have increased replicative capacity in vitro -- both in the presence and absence of drug. Yet another chink in the armor of that old wild-type-is-wild-type-because-it's-the-most-replicatively-fit saw. Darwin be damned!

  • Tom Merigan, Bob Shafer and Sarah Palmer (Stanford) looked at the effect of hydroxyurea and ddI against ddI-resistant isolates as well as the effect of hydroxyurea in combination with other adenosine analogues (i.e., adefovir dipivoxil and PMPA). The concentration of hydroxyurea used was 50 micro-molar. (Clinical equivalent of 500 mg BID.) At this concentration the didanosine IC50 value for WT virus was reduced 8-fold, for MDR HIV was reduced 17-fold and for MNR HIV was reduced 22-fold. The adefovir IC50 was reduced 8-fold, 4-fold and 5-fold, respectively. The PMPA IC50 was reduced 26-fold, 6-fold and 35-fold, respectively. Increasing the HU concentration to 100 micromolar reduced the adefovir and PMPA IC50 values for all three isolates to levels <0.05 micromolar.

  • A paper by Hamburg's Jan Van Lundzberg looked at the restoration or preservation of lymph node architecture and found significant differences between those patients treated with PI-containing regimens and those patients treated with only nucleoside combination regimens. The former showed in tact lymph node architecture while the nuke only group did not. This phenomenon is said to not be solely a function of the perhaps superior potency of a PI-containing regimen. Work to investigate the effect of the non-nuke RTIs on lymph node architecture is underway.

  • Famed Brigitte Autran's plenary talk was entitled "Immune Restoration with HAART in Established HIV Infection" ("established" because the mean baseline CD4 cell count in her 317 "highly pre-treated" [but PI naive] patients was 47 cells/mm3; mean baseline plasma viral load was about 5 logs or 100,000 copies/mL). After her talk, Giuseppe Pantaleo cautioned the deceivingly coy Autran not to generalize her restorative observations (which now have quite clear limits) to the whole of HIV-infected patients (i.e., less advanced ones). What seemed to rub the ever-incomprehensible (Can't someone send him to an accent reduction workshop?) Vaudois immunologist the wrong way was Autran's conclusion that the "slope" of immune recovery in her cohort was only 10-20% and that she believes that if complete immune restoration is possible it would require 4-8 years (her range, honestly). One of the moderators of the session, either Tom Merigan or Joep Lange, noted that since the immune damage had taken, on average, some 10 years to accumulate, it was not at all surprising to learn that it might take a comparable time period to repair. Giuseppe reported that in his hands, "earlier" patients who were treated for 48 weeks with ABC+AMP have shown "complete recovery" of T cells in both blood and lymph. He did not elaborate -- but the results were recently published in Nature Medicine.

  • In a cohort of long-term non-progressors from the ANRS, Autran looked at immune responsiveness to a series of antigens (or epitopes): HIV-gp160, HIV-p24, streptococcus, PPD and candida. When the LTNP were grouped (somewhat arbitrarily) into those with consistently "low" plasma viral loads (<200; mean 50 copies/mL; range 20-170 copies/mL) or variably low/moderate (my language) (mean 11,400 copies/mL; range 210-860,000 copies/mL), only the group of LTNPs with consistently low plasma viral loads showed evidence of an anti-HIV-gp160 and anti-HIV-p24 immune response. À la Bruce Walker, she postulated that the HIV-specific CD4 cells are either eliminated (very early) by CTL or by chronic activation and eventual deletion via apoptosis. She then showed a slide entitled, "Dendritic cells can rescue CD4+ T cell responses against recall and HIV antigens in LTNPs." She questioned whether the T cell responses (in these LTNPs) against HIV are truly effective or merely markers for disease progression. (Autran appears to believe they are merely markers.) During the discussion the questioned was posed, "Do you believe recovery of the HIV-specific immune response would be faster in earlier patients?" Autran said that they had a cohort of patients who were treated (with HAART?) during primary infection and that no recovery of the HIV-specific CD4 response was seen. [At this point Franco Lori got up (again) to tell us that in his ddI+HU study 6 of 12 (50%) patients, after 2 1/2 years of treatment, had recovered their HIV-specific T helper response. This, he said, has been conducted in collaboration with Bruce Walker. Guiseppe said that in his experience 40-50% of patients treated within 3-6 months of infection get "some recovery" of HIV-specific T help. Franco said that in his study of ddI+HU+IDV 90% of patient have recovered their HIV-specific CD4 cell response. "If we treat later than that," he warned, "we lose everything."]

  • Gladstone's Joseph (Mike) McCune presented a great plenary talk about T cell production and the relative contribution to this of the thymus. Using computerized tomography, radio labeled cells and an ultra mod "stable isotope/FACS/GC-MS Technique (see PNAS 2/98 for complete details), McCune looked at the association between evidence of "abundant thymic mass" and age and baseline CD4 T cell count. In what was one of the few encouraging papers of the 4 day summit, McCune showed that while age did have an effect on the ability to detect abundant thymic mass, even at age 39 and older some 50% of volunteers showed evidence of "abundant thymic mass." In those 39 and younger (with baseline CD4 T cell counts 300-500), he saw evidence of thymic function in a full 90% of individuals.

  • Australia's Don Smith seems to have done the Bruce Walker experiment (Actually, Giuseppe, Brigitte, and Franco -- and undoubtedly others -- will soon have data to share with us) treating patients with acute seroconversion with various HAART regimens in order to try to preserve the HIV-specific CD4 T cell response and either abort the infection or turn patients into long-term non-progressors. Smith studied 33 acute seroconverters, 16 who were treated and 17 who were not. There were no Western blot bands in 5 and 8 or these patients, respectively; "most" were p24 antigen positive; and the duration of seroconversion symptoms were 19 days in the treated group and 8 days in the non-treated group. Median follow-up was just over one year (56 weeks). Smith and colleagues looked at memory and naïve CD4 and CD8 T cells. In the treated patients they saw a rapid drop off in CD8+ T cell activation -- which falls but does not go back to normal (as it does in Epstein-Barr virus infection, for example). Smith believes this is probably evidence of continued presence of antigen -- but that it could also be that the CD38+HLA-DR+ cell population is simply slow to recover. An important distinction was made between continued "presence" of antigen and continued "replication" of virus. And it remains to be seen which accounts for the continued elevation in activated CD8+ T cells. Smith concluded that aggressive treatment during (or prior to) seroconversion may be able to change rapid progressors into slow progressors but not into HIV negative. Maybe there is no "morning after" afterall.

  • Where you might have expected reports of reservoirs and flushing plans -- ways to identify privileged sites and ways to expedite the turn-over of Finzi, Wong and Chun's (a.k.a. Siliciano, Richman, Fauci) now notorious 3rd compartment -- the "eradication" session of this meeting was composed only of three papers contradictorily concluded that 1) No, there is no evidence of viral evolution in these latently infected CD4+ memory T cells; and 2) Yes, there is evidence of viral evolution -- even in patients suppressed to < 20 copies/mL. Sample sizes in all three presentations were small. UCSD's Wong, from Richman's group and the only one to argue against evidence of evolution (Miguel Martinez had 1 patient with evidence of evolution and 2 patients who did not), went at great lengths to explain that his results pertained only to "this certain type of cell" and that he could not say from his data whether or not there might be on-going virus replication in these patients -- occurring in other cell types or other compartments of the body. "I would not make those claims based on these data," he said.

  • Franco Lori's latest hydroxyurea presentation was the little-train-that-could which kept chugging up that steep mountainside trying, again in vain, to garner the respect of his fellow investigators. Lori, in collaboration with Bruce Walker, Eric Rosenberg and Judy Lieberman, showed rescue of HIV-specific CD4 T help in 6 of 12 ddI+HU (chronically infected) patients for whom he had long-term (122 weeks) follow-up. "This is the first time this had been reported in chronically infected patients," Lori announced. Charles Boucher immediately jumped up to the mike to challenge Lori with the thought that HU is probably doing nothing antivirally -- not even decreasing the IC50 of ddI-resistant HIV -- but rather simply reducing the number of target cells. Later Andrew Phillips rose to argue that since HU's usefulness (if it has any) is probably not of the virus-inhibiting variety, surrogate marker studies designed to measure antiviral efficacy are not appropriate and that a large, clinical endpoint study is needed.

  • Maria Pia De Pasquale of Harvard/Mass General presented the results of ACTG 347: amprenavir+AZT+3TC vs. amprenavir monotherapy. (An earlier version of these results had been presented in Chicago earlier this year.) Of course, AMP looked good in the study, and 15 participants developed mutations associated with reduced sensitivity to other protease inhibitors. (The good news, according to De Pasquale, was that only 4 of the 19 patients on AMP monotherapy developed the I50V amprenavir mutation. The mutations at 10, 20, 46, 82 and 84 which arose seemed to escape her notice.) What's weird and potentially interesting in her abstract -- but not addressed in her oral presentation -- is that 3 of the 7 failures on the triple therapy failed with no signs of genotypic resistance to 3TC or AMP. (All study patients were 3TC and PI naive.) Three additional triple therapy failures showed signs of only 3TC resistance (the M184V mutation). According to the abstract, "this suggests that factors other than drug resistance can initiation failure of triple therapy." Diane Havlir made the same heretical proposition in her updated analysis of ACTG 343: rebound of indinavir sensitive virus while on AZT+3TC+indinavir. While Doug Richman heralded this as necessitating "a fundamental paradigm shift," most of the others who spoke (including Trilege's Françoise Brun-Vezinet) saw nothing odd in this observation.

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