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Breakthrough

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tagline 1999

High-Technology Betrays Its Dark Side As Researchers and Patients Struggle to Interpret the Noise


'AIDS is back'

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.

About Face

"When it comes to bacterial and fungal infections, wherever there is treatment, we don't accept a little bit of positive blood cultures. We happily accept that with HIV. Where's the difference here? Infectious disease has taught us for years -- especially with severe infections like systemic fungal infections, bacterial, TB -- you treat it early and you treat it at the outset with everything you've got."

David D. Ho, M.D.
July 15, 1996

"Patients with a little virus [rather than none] have the best [CD4] proliferative response [to HIV]."

David D. Ho, M.D.
January 18, 1999

"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.