When queried about his take on the Chicago retrovirus meeting and the state of HIV clinical care at large, a relatively high-profile-if arriviste-Floridian AIDS doc reassures with his characteristically deliberate, trancelike articulation, "The good news is that those patients who are doing well on therapy will continue to do well for a very, very long time." The next day, Merck presented the 3-year follow-up on its nearly beatified "035" study: reported response rates had fallen from the near 90% mark to somewhere around sixty percent. At last, the official drug company press releases were beginning to reflect what many AIDS docs had been seeing in their practices for some time. Has the bubble of therapeutic euphoria begun to burst?
In this issue of TAGline, Mark Harrington describes his (and that of two of his colleagues) recent roller coaster ride on the antiretroviral therapy express, imparting a degree of candor seldom found in these pages. Reflecting upon yet another recent death of a longtime friend and comrade -- along with the debilitating consequences of another friend's best-faith efforts to escape that very fate -- Mark notes that, even if he has ducked the axe this time around, it is only a matter of time before resistance comes calling.
"Call the doctor's office." That terse message greeted me upon my return from the Glasgow pharmaceutical drug fair and the European AIDS Treatment Group's Southern States activist training meeting in Rome last November. It could only mean one thing.
I'd had blood drawn before my departure, but hadn't had time to pick it up before leaving. After two years of maintaining a viral load beneath the limit of detection (most recently, just before Geneva, <25 copies/ml), my viral load had spiked up to 5,379 copies. Breakthrough! I phoned the doctor's office.
"You should probably come in and have a repeat test," the office manager told me dryly. I freaked out. The obsessive discipline of triple therapy taken thrice daily had worked for just two years and then, apparently, failed. My first antiretroviral regimen had petered out, and I was on my way back down the slope towards you-know-what.
The reactions of my friends and colleagues were like Rorschach blots of their own stance towards the epidemic. "It's just a blip," Spencer Cox reassured me. "[My doctor] sees these all the time."
"It's a viral breakthrough," said Gregg Gonsalves, TAG's house pessimist. "You should try an easier regimen."
"It's just a blip," my doctor seconded Spencer's comforting assessment.
"Should I get a resistance test?"
"You could probably get one a lot sooner from your other doc than from me. In the meantime, we'll take blood for another viral load."
The December viral load came in at 1,656 copies -- down half a log, but still detectable. No clues there.
"It's probably a breakthrough -- I'd guess to the 3TC," my other doctor hazzarded. "Come in and I'll take some blood."
Well, if my virus was just resistant to the 3TC, I suppose I could keep on taking my d4T and my protease inhibitor, and add another nucleoside, say, ddI and hydroxyurea. (Why not? It couldn't hurt; my T-cells were in the upper three figures.) Just before Christmas I had had blood drawn for a phenotypic resistance test. They promised results within two weeks. I spent the time wondering what I'd have to switch to, and wondering who I should tell. What if it was just a false alarm? Had I been non-compliant? Was the test any good?
FedEx screwed up the shipment, so on December 28 I had to go in for another blood draw. The company also wanted input on what price they should charge for their new test. The competition (LabCorp/Virco, offering a joint genotypic/phenotypic test) charges upwards of $900 for their product. I told them that they had to charge less than $500 a test if they wanted their assay to be widely used. Look at Merck. They charged the lowest price of any protease inhibitor maker, and grabbed lots of market share. Anyway, the state ADAPs were nearly broke just keeping up with the prices of Sustiva and Ziagen, each the most expensive in its class. They drew another tube of blood.
The new year started out badly. Paul Corser, a longtime survivor and colleague at AmFAR, died on January 4th. Paul had helped run AmFAR's community-based clinical trials network and had been a key TAG ally in persuading AmFAR to fund immune reconstitution and vaccine research. That same week, one of my good friends called to tell me that, after a year-long drug holiday, his T-cell count had come in at a disastrously low level. (He hadn't had any options, so he decided to stop and wait -- in some overly eager famous AIDS sage's 8/96 words, "for the landscape to change." It hadn't.)
Upon the advice of his doctor, he started a kitchen sink regimen, "mega-HAART": four old drugs and three new ones. Seven all told, including the latest to arrive with a generously financed flourish, Dupont's efavirenz (Sustiva). According to him, the Sustiva was like a bad trip. After reluctantly embracing the fickle promise of "mega-HAART," he'd spent the better part of a month more or less immobilized while his body struggled to adapt to the overwhelming chemotherapy. Facing mortality in the eye -- and with intolerable side-effects from the drugs which were supposed to avert that very mortality -- he took two weeks off and explored the fine print of his company's disability policy.
Just before taking off on yet another SAD-defying solsticean dalliance, Peter Staley called. "We seem to be on a parallel track," he said. (We'd started our identical HAART regimens, Crixivan+d4T+3TC, on the same day in August 1996.) "I just broke through: 1,600."
"Well, it could be just a blip," I said, unconvincingly mimicking Spencer in November. Gregg Gonsalves took Peter for a resistance test just before they left for two weeks in the sun.
Later that day, I got my resistance results back. "I'm looking at the results here on the screen," my doctor explained, "and trying to figure out how to print them out. They were able to grow out virus [from your sample] but there's no evidence of resistance to any [of the 15] drugs on the panel."
"What could that mean? Steadily detectable virus without any sign of resistance to any of the drugs I'm on?"
"We're seeing more and more of this," he said, stumped as to why, and as to where the wild-type virus could be coming from. (In fact, breakthrough of wild-type virus, first seen in ACTG 343, and again in the French Trilège study and in an early amprenavir study (ACTG 347), had been extensively reported on early last summer at both the Lago Maggiore resistance workshop and in Geneva. At the time, only a minority of alert virologists paid the report its due respect, and a handful of theoretical explanations were tossed around. No one, however, has yet been able to quite square this phenomenon with the generally accepted model of HIV pathogenesis and viral kinetics.)
"Should I intensify [my therapy]?"
"Why don't you come in and we can talk about it?"
So on Martin Luther King Day, I braved a pounding rainstorm to make yet a third trip to try to sort out this viral breakthrough nightmare. My doctor handed me the phenotype printout. Both my virus and the wild-type control virus had been tested for sensitivity to fifteen antiretroviral drugs. The results were then plotted together on the same pair of axes. There was my viral resistance pattern, plotted out as a sinuous blue line snaking along in tandem with a red line: that of the wild-type control virus. For now, the lines tracked closely together. But one day they would diverge, and I would face the consequences. In the meantime, it was instructive to observe just how destabilizing a simple viral hiccup could be.
I returned downtown and began writing. Science is making progress, but my friends aren't. That's the paradox of our work. I'm safe for now -- still sheltered under the umbrella of privilege accorded to those of us who started therapy still antiretroviral-naïve and who have access to the new technology and latest information. But safe for how long? Small, incremental discoveries in the immunologic sciences were fascinating, but were not going to get a new HAART regimen for my friends. Or make the drugs less inadequate, less expensive or less toxic. Last week I was having dinner with Barbara Hughes, our board president.
"The euphoria's gone," I said, "and, for a lot of people, so is the urgency."
"We feel it [the urgency] because of [the experiences of our friends]," she replied, "but it's not like the old days." AIDS is back, not with a bang, but a whimper.
Continual Suppression to Yield to Pulsed Therapy?At the Keystone HIV Pathogenesis symposium in January 1999, the Aaron Diamond AIDS Research Center's Douglas F. Nixon presented a paper entitled "Temporary Containment of Viral Replication After Cessation of Antiretroviral Drug Therapy." He reported on 4 individuals from one of the ADARC's primary HIV infection (PHI) HAART studies. They had been only intermittently (about 50%) adherent, but viral load and immune responses were measured throughout their drug holidays as well as their on-treatment periods. Each time they stopped taking therapy, their viral load spiked up, but immune cells -- HIV-specific CD4+ T-cells and cytotoxic T-lymphocytes (CTLs) -- moved in to contain the virus. Eventually, after several such cycles on and off treatment, 2 of the 4 stopped therapy altogether. Their viral load rebounded but was, once again, quickly contained by the immune response. One remains off therapy with a viral load beneath the limit of quantification (<50 cells/ml) after a year off HAART, and one is 4-6 months out. There were no reporters at Keystone, so it took a few weeks for this story -- surely one of the most important developments of late -- to percolate out; it was ultimately broken by Mike Waldholz of The Wall Street Journal on January 25, with the appetizing title "Cocktail Break."
Seeking to pursue these findings further, the ADARC researchers opened an IRB-approved study in which people who have maintained viral load below 50 copies/ml for over 2 years, and who have both HIV-specific CD4+ and CD8+ CTL cells, can elect to go off HAART and be followed closely for viral and immunological responses. So far, 2 additional individuals -- each treated during PHI -- have been able to maintain viral control after stopping therapy. Their viral rebound was slower than in natural infection, with a doubling time of four days rather than one, but it eventually rose to baseline before a vigorous immune response reduced it once again to beneath the limit of quantification. Five more individuals, some acutely and some chronically infected, are now being followed in this "Stop HAART" study. Unlike Bruce Walker, the ADARC researchers have been able to identify HIV-specific CD4+ cells in both acute and chronic infection, suggesting that they may be recoverable if immune reconstitution is sufficient. (France's Brigitte Autran still stands fast at 6-8 years for sufficient immune recovery.)
Intriguingly, "Patients with a little virus [rather than none] have the best [CD4+] proliferative response [to HIV]," commented Ho. It appears that these individuals may have successfully immunized themselves against HIV, at least in the short-term, under cover of HAART. Their CD4+ cells still harbor substantial HIV provirus, but it appears that whenever the virus is turned on the immune system is able to control it -- for the time being. They will have to be followed for life, however, as any immune stimulus, whether it be an immunization, an infection, or the immune deterioration associated with age, could be sufficient to overcome this temporary immune control of HIV.
About one year ago during the jointly co-sponsored TAG/AmFAR "reservoirs" meeting at MIT, Donald Mosier, a mouse researcher at The Scripps Research Institute (La Jolla, CA) first proposed in public the then heretical proposition of cycling patients on and off antiretroviral therapy (see "Reservoirs Dog," in the 5/98 TAGline). Over the summer, San Francisco's Steve Deeks had also recently begun to privately embrace the prospect of pulsed therapy. The idea last winter was that, in the face of waning immune responses due to the absence of sufficient antigen to maintain effector cell functions, antigenic stimulation was needed. Where ADARC researchers and others suggested periodic immunization with various synthetic HIV vaccine products, Mosier lambasted Ho and Markowitz's unnecessarily complicated approach, challenging his colleagues thusly, "It surprises me that you're actually thinking about vaccines [to boost immunity] when you've got the natural infection of immunized people to begin with." Tufts' John Coffin also found the vaccination proposition preposterous.
In the meantime Italy's controversial Franco Lori, after perhaps stumbling onto a winning treatment schedule in his (and Berlin's Heiko Jessen's) clinical practice, has been experimenting with the idea of periodically suspending antiretroviral treatment for increasing intervals of time -- after an (as yet undefined) sufficiently recuperative initial period of viral suppression. The goal: to eventually "teach" the immune system to control the virus on its own. Lori's (still entirely experimental) renegade approach has been dubbed, "Start, Stop." As of the Chicago retrovirus meeting, the number of reports of patients successfully stopping therapy still totaled fewer than a dozen -- and this was almost exclusively among individuals treated during primary infection. The ratio of success to failure appeared to hover around 1:1.
While precious little has changed on the HIV vaccine front since last summer, when California-based VaxGen received the go-ahead to proceed with a Phase III "field" trial of its gp120-based AIDSVax (B/B') product in North America, the recent deluge of vaccine headlines would seem to have it otherwise. Early last month, a wave of press releases heralded the commencement of a large, 4-yearlong Phase III vaccine study in Bangkok, also with the VaxGen (B/E) product. Similar fanfare was paid to the announcement, later the same month, of a tiny yearlong study in Uganda -- using a vaccine based on the Euro-American clade B strain! To put all these feel-good vaccine pronouncements into perspective TAGline called upon Christopher Barillas, a plugged-in "new media" huckster whose daily take on the news can be found at Mediapolis' datalounge.com web site. Barillas is currently taking part in a multicentered Phase II study of the "prime boost" ALVAC canarypox+gp120 vaccine products of Pasteur Mérieux Connaught, and Chiron.
The most highly publicized HIV vaccine candidate -- and the furthest along through the clinical trials labyrinth -- is the recombinant gp120 product of Genentech, reborn in 1995 as AIDSVax after Genentech's HIV vaccine unit was spun off as VaxGen. When this rgp120 product came up before an NIH review panel in 1994, the group of experts voted against the vaccine's proceeding to Phase III trials, and a small storm of protest ensued.
CDC veteran Donald Francis, then employed by Genentech, made it his personal mission to see that the decision was overturned. And after tinkering with the product back in his California laboratory (adding a second epitope to the immunogen thereby rendering it "bivalent" and more likely to be effective against the major HIV strains common in the U.S. and Europe), Francis got his wish. Detractors of the vaccine crusader and his multi-year campaign to promote AIDSVax as a viable HIV vaccine weren't quite able to silence the triumphant press blast that greeted the official commencement of Phase III trials in the U.S. late last December.
In a December 21 story, The New York Times accompanied Troy Masters, publisher of the biweekly newspaper LGNY (Lesbian and Gay New York), as he signed his name to consent forms, stripped down to a hospital robe and joined those lining up to volunteer for the "world's first full-scale test of a vaccine to prevent AIDS."
"The virus needs a vaccine," Masters earnestly told Times reporter Lynda Richardson. "If there is a front of activism that needs to be developed that's it. To that end, I'm giving my behavior over to science. This is like signing for permission to end the AIDS crisis."
In his own January 14 cover story for LGNY, entitled "AIDS End Game," Masters declared his participation in the Phase III AIDSVax trial the beginning of the end of the epidemic and threw himself into the ring as a soldier in the fight. "The end of AIDS comes in stages," Mr. Masters wrote. "A vaccine is the end game." But how close are Francis -- and willing media savvy volunteers like Mr. Masters (he was also featured on UPN 9 News at Ten) -- to developing a viable vaccine?
There is a well-grounded belief among leading AIDS immunologists that an HIV vaccine that does not induce a strong cellular immune ("CTL") response -- and Francis' does not -- are a waste of time and money. "Seriously wanting" is how Dr. John Moore of the Aaron Diamond AIDS Research Center rates the AIDSVax vaccine in a July 1998 interview with POZ magazine. "I'm absolutely certain that the vaccine's efficacy will be immeasurably low," he said. "There is also a moral issue," he adds, arguing, "It's simply not appropriate to immunize human volunteers with a protein that has no chance of protecting them from HIV."
That's right: "no chance." Not that the prime boost trial I'm in stands a significantly greater chance of wiping out the epidemic. But it's only a Phase II, and the ALVAC+gp120 prime boost approach has shown at least some ability to stimulate both the humoral and cellular arms of the immune system -- even if, for some reason, about one third of the vaccinees don't seem to develop any CTL response (see table). Besides, the organizers of the ALVAC prime boost trials are hardly declaring it the AIDS "end game."
The world was a darker and scarier place in October 1994. I was at the tail end of 29. I'd lived in New York for four years and had been more sexually active living than would have been possible where I grew up. I'd been careful but not perfect, and I hadn't been tested in six years. I had a raised purple welt on my hip. I was living one paycheck to the next and had no health insurance.
A friend told me about a group called Project ACHIEVE which gave gay men free HIV tests. "The hardest thing they'll ask you is how many men you've slept with in the last six months," he said. I thought he was kidding. Two weeks later I got the negative result and a pitch to join a study monitoring the sexual habits of high risk HIV negative men. In a rush of relief and gratitude I agreed.
Project ACHIEVE is a clumsily constructed acronym which stands for AIDS Community Health Initiative Enroute to a Vaccine Effort. My consent enrolled me in the Vaccine Preparedness Study (VPS) of the HIV Network for Prevention Trials (HIVNET). VPS was created to gather baseline data for future vaccine trials. The organization has offices in Manhattan and Brooklyn with major outreach programs directed at gay men, female and male IV drug users, and the girlfriends of male IV drug users.
The most frequently cited motivations for participating in the VPS are "helping to find a vaccine that works" (93%), followed closely by "helping to stop the epidemic" (91%). I'm not sure what the difference is between the two. Still, it's nice to see that there are good-hearted people out there sufficiently committed to the cause. Then again, good intentions pave the road to hell. Something like that. Maybe our hopes, as some have suggested, are ahead of the science. But maybe that's alright. So are our needs.
According to the New York Blood Center, the principal social concern listed as very or somewhat important in influencing the decision to participate was vaccine induced seropositivity (70%) and the impact a positive HIV-1 antibody result from a conventional serologic test could have on the study participant. Of these concerns, the most frequent was the fear the false-positive could affect health or life insurance decisions (56%) or lead to problems traveling to foreign countries (41%). An obvious concern, conspicuous by its absence, is that participation in an HIV vaccine trial in 1999 will likely disqualify a person for later participation in a trial of a, perhaps, more promising candidate. Once you give up your immunologic virginity, you never get it back.
Over the next two years, I came back every three months and went through the same routine I went through my first day in the office: How many sexual contacts have you had since your last visit? How many of those contacts were with men who were positive or whose HIV status you didn't know? Have you consumed any of the following controlled substances? Et cetera.
Through it all, changes were taking place at the group's Union Square headquarters. The offices moved from four cramped rooms to nearly 10 on a higher floor. Staff rippled in and out with funding tides. Most of the motivational posters trumpeting the joys of "hot" safe sex that reached a daring vogue in the early nineties were eventually moved out of sight. Once in a while though, a naked butt on a motorcycle seat with something roaring above it in Dutch will appear in a private office. It seems almost quaint.
The staff, almost all gay men when I joined, is almost all women now, professional competent women hailing from a variety of health and social science backgrounds. Joy Behar could broadcast a brilliant View segment from here. "Excuse me, I just reached into the candy jar for a butterscotch and came out with a packet of lube, a ribbed condom and a phone number for Eduardo. Where do I sign?"
According to Dr. Beryl Koblin, who co-authored a participant study for the Laboratory of Epidemiology at The New York Blood Center, a solid majority of VPS participants (77%) indicated they would definitely (27%) or probably (50%) be willing to participate in a randomized vaccine trial. I was among the 27% who were called back.
On the morning of October 7, 1997, I was greeted at the door by a crowd of smiling, slightly nervous people welcoming me as the first person in the program to receive injections testing the effectiveness of the two experimental vaccines, vCP205 (ALVAC) and gp120 (AIDSVax). A photographer took several pictures at awkward moments (hugging someone I'd never met, taking my shirt off, having my blood taken). I remember accidentally breaking the clinic's scale, twisting the retractable arm off the height meter. Someone dashed in and whisked it out of sight. Another picture flashed.
In earlier trials, the two vaccines were given sequentially, but the trial I'm in delivers the ALVAC primer vaccine (vCP205) simultaneously with the gp120 booster -- even though previous studies have shown that sequential immunization (that is, immunizing with the canarypox vectors and then later with the gp120 boost) appears to generate slightly higher levels of CTLs. Last month I received the last of my injections. Now I wait. The trial is double blind, so I have no idea whether I am getting two placebos, the ALVAC primer and a placebo, or the ALVAC primer and the Chiron gp120 boost. For all I know, I could be receiving two placebos, but that's the way clinical science works. In order to tell if the vaccine is doing anything (good or bad), you've got to have a group against which to compare it. I find out what I've been given in October.
According to materials published by the National Institute of Allergy and Infectious Diseases, this prime boost vaccine approach currently appears to show the most strategic promise (which, admittedly, isn't saying a whole lot) among current HIV vaccine candidates for eliciting cytotoxic T lymphocyte (CTL) responses against HIV and inducing neutralizing antibodies.
Trouble is, there's no telling how protective these antibodies will be against a strain of HIV I might encounter in real life. As for the CTL response, most studies show it to be short-lived. In two studies of ALVAC vCP205 presented last summer in Geneva, only 30-40% of vaccinees had detectable CTLs at each point of measurement. 65-75% had CTLs at at least one time point. After four immunizations, the number of vaccinees with newly detectable CTLs appears to level off. Animal data are sketchy at best. So-called "challenge" experiments, where an immunized chimpanzee is intravenously infected with HIV after completing the required series of vaccinations, almost without exception evaluate the vaccine's efficacy at a time when antibody and CTL responses are at their peak -- and often with the exact same strain of HIV from which the vaccine was manufactured. Hardly a real world scenario.
ALVAC vCP205, developed by the French biotech company Pasteur Mérieux Connaught, uses an attenuated canarypox virus to carry copies of parts of several HIV genes coded for the following proteins: the envelope protein rgp120 (MN strain); the protein that anchors gp120 in the envelope, gp41 (LAI strain); gag, a gene that codes for p55, the core protein (LAI strain); and pol, a gene that codes for the HIV enzymes (LAI strain). The gp120 booster in this study, for better or worse, is the Chiron product. Whereas earlier prime boost studies also used the gp120 immunogen of Chiron Corp., future studies -- including VPS -- will be using VaxGen's AIDSVax. According to Pasteur Mérieux's Michel Klein, the reason for the switch is that the VaxGen bivalent gp120 is derived from a primary HIV-1 isolate, whereas the Chiron gp120 is not. The ability of the canarypox vector to induce immune responses to the HIV core protein, gag, is thought to be of critical importance. Early data suggests that approximately half of vaccinees have measurable CTLs against HIV gag and env one year after the last immunization.
People that have experienced what I have experienced ask what motivates me to volunteer for an HIV vaccine study. I've been surprised by that. I learn more about them from their question than I could tell them about myself with an answer, but there's no need to rub it in, so I don't. Genuine humility is a hot commodity these days -- like Jesus Christ headlining in Las Vegas -- so I'm not going to try to sound humble and meek and self-sacrificing. Let's just say that it's not difficult to be altruistic in a selfish world when well-meaning people make it easy for you and draw up the papers for you to sign. I'm not so rare a bird as you might think. If you can't buy that, you can always go with the free publicity angle.
Status of Current HIV-1 Vaccine Strategies:
|Potency of Elicited Immune Responses||Other Undefined Protective
|Live attenuated virus||Yes||Poor||Emerging Evidence||Some evidence|
|Killed virus||Limited||Poor||Negligible||No evidence|
|Envelope subunits||None||Poor||Negligible||No evidence|
|Vaccinia or avipox prime/boost||None||Poor||Weak||No evidence|
|DNA prime/boost||Limited||Poor||Weak||No evidence|
|Source: Nature Medicine (vaccine supplement), May 1998