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Farewell to Arms

tagline May 2001

Government Experts Roll Back the Big Guns, And Slither Away to Trenches

‘Inferences, hints and clues’

Mark Harrington writes, “As someone who’s spent the last twelve years of my life trying to encourage more and better AIDS research, and has worked with community groups to help push Congress and three Presidents to provide more resources for that research, it’s profoundly disappointing that the leaders of the research effort—both at NIH and in the lavishly funded AACTG and the smaller, but still substantial CPCRA—have signally failed to do anything more to address the question of ‘When-to-start?’ than to reluctantly replace one set of guidelines based on expert opinion with another.” His brief history of where we are and how we got here is now up on the TAG web site and excerpted below.

A newly revised set of U.S. government guidelines on when to start antiretroviral therapy, despite repudiating the “Hit early, hit hard” strategy which has predominated in the U.S. since the Vancouver AIDS conference in 1996, merited only a peripheral presence at the 8th Annual Retrovirus Conference held in Chicago from 3-8 February 2001.

Highly active antiretroviral therapy (HAART) should be offered to every HIV-infected individual with a(n):

Previous HHS Guidelines

New HHS Guidelines

CD4 <500/mm3 or HIV >20,000/mL CD4 <350/mm3 or HIV >55,000/mL

Neither the chairs of the Health and Human Services guidelines panel nor the organizers of the Conference appeared especially eager to highlight the significant modifications that appeared in the February 2001 update of the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults & Adolescents.

Prior to the conference I heard a rumor that the organizers had turned down a request by guidelines panel co-chairs Anthony S. Fauci (NIAID) and John Bartlett (Johns Hopkins University) for a press conference to announce the new guidelines. So, at the opening press session I questioned Retrovirus chair Connie Benson of the University of Colorado whether they had indeed turned down a request by Drs. Fauci and Bartlett. “Not at all,” said Dr Benson, who is also a co-chair of the government’s top HIV clinical research program (the AACTG). It turns out the only request she heard had come from a NIAID press person. “Do you think I would actually turn down Dr. Fauci?” she asked. And in fact, as the conference opened, the only document NIAID had shown the conference organizers was an anemic two-page press release; the Retrovirus press person had to download a copy of the new guidelines from the internet.

Why the low-key reception? Well, just as enthusiasm for the early use of AZT was deflated by the release of the Concorde study results in 1993, so the 2001 treatment guidelines finally depose the ailing “Hit early, hit hard” strategy. But for some, old strategies die hard.

Rather than trumpeting the changes by holding a press conference before the world’s leading AIDS reporters in Chicago and admitting “Whoops! We were wrong! We screwed up! Maybe treating everyone with a viral load over 5,000-10,000 HIV RNA copies/mL wasn’t such a great idea after all,” the guidelines panel cochairs and the Retrovirus organizers all felt it was more opportune—or more expedient—to skate over the matter as casually as possible, as though the new guidelines represented a simple and relatively uncontroversial recalibration of the standard of care.

An honest mistake?

Of course, TAG has been covering this controversy for a long time. When Mark Schoofs from The Wall Street Journal called me, he said, “This is a good thing. People don’t have to go on therapy so early.”

“Well, yes,” I said, “but it would have been much better to have a clear answer from a randomized, controlled trial by now.”

“Well, Tony Fauci says that’s unfeasible.”

“Well, if he says so, it must be true,” I replied, “but if they’d started one in 1996, we might have an answer by now.”

“You sound angry.”

“I am angry. Thousands of people were put on therapy too early, and some of them developed life-threatening side effects, or resistance, and they would have been fine if they had just waited.”

Was not seeking evidence for such a sweeping policy simply an honest mistake— a gush of euphoria that the long, dark night of AIDS was finally over? Well, of course, those promulgating the original standard of care were sincere—but they also defaulted from their obligation as scientists to prove that their expert opinion was actually correct. Considering the emergence of long-term side effects and widespread cross-resistance, it would seem that it was not.

So why change now?

The death of the eradication hypothesis?

The NIH press release distributed at the conference quoted Dr. Fauci as saying, “We know that we cannot eradicate HIV infection with currently available medications.” But we have known that HAART cannot eradicate HIV ever since the discovery at the laboratories of Bob Siliciano, Doug Richman, and Tony Fauci in 1997 of latent HIV reservoirs in resting, provirally-integrated CD4 cells. The original HHS guidelines came out that same year. So the “Hit early” approach could not have been based solely—or even mainly—on the feasibility of eradication.

Treat HIV like any other infectious disease?

In the minds of some, the “Hit early” approach was based on the idea that, in Bruce Walker’s words, we should “treat HIV-1 like any other infection— treat it.” Well, sure. The question is, when?

HIV-1 is not like other infections. Some, such as bacterial infections, can be cured with antibiotics. Obviously, if HIV could be cured, we would try to cure people. Persistent viral infections, such as herpes, cannot be cured, and we do not treat them chronically; instead, we only treat them when outbreaks occur. HIV is like neither bacterial infections nor herpes. It cannot be cured. It is chronic and persistent. And it never goes into full latency—unlike herpes. Treatment requires complex, expensive, sometimes toxic, combination therapy. Full adherence is difficult if not impossible. The development of drug resistance is a constant threat.

Solid results from evidence-based medicine?

In the NIH press release, Fauci went on to say that the revised guidelines present “evidence-based recommendations for initiating antiretroviral therapy that take into account both the benefits and potential risks...” But the guidelines themselves admit that, “The optimal time to initiate antiretroviral therapy is not known.”

The “evidence” to which Dr. Fauci referred is a random grab-bag of observational studies which are contradictory and hardly definitive. One can conclude whatever one wants to from these observational studies: if you favor early treatment, you can find studies that do too; if you favor later therapy, other studies will back you up.

Weaker evidence from observational studies?

Observational studies, despite their limitations, are practically the only “evidence” we have right now about the clinical benefits of various starting thresholds. Several large cohort studies presented at the Retrovirus conference in February 2001—most of them in poster form because they did not fit the preferred weltanschauung of the conference organizers—suggest that, while starting when the CD4 count is below 200 is clearly less effective than starting when it’s above, there is no difference among groups starting with higher CD4 cut-offs. Even very high viral loads may make little difference.

What next?

It would be nice if we could really have treatment guidelines based on evidence from well-controlled studies. But perhaps we missed the chance to initiate such studies because so many were captivated by the euphoria that accompanied the adoption of HAART after 1996. Sometime in 1997, when David Barr and I were in Anthony Fauci’s famous corner office at NIAID, we asked him to support a major clinical trial of when-to-start. “It’s the most important question in HIV therapy,” he agreed. But nothing happened. During the 1998 adult AIDS Clinical Trials Group (AACTG) recompetition, NIAID once again missed the opportunity to encourage—or force—the research community to address the question.

In early 2000, after considerable activist pressure, NIAID’s Division of AIDS appeared to recommend $42 million in funding for a when-to-start trial and held several workshops to discuss methodology and feasibility issues. These initiatives were smothered in the cradle by AACTG leadership and community representatives who dismissed the feasibility of longterm research. This round of when-to-start ideas was finally buried at the NIAID Council meeting in January 2001.

As the press started to get hold of the new treatment guidelines, it was natural to ask Dr. Fauci why there were no clinical trials to answer what appeared to be such an important question. Even though the NIAIDsponsored feasibility studies had yet to be completed, Fauci told ABC News, in a story aired on January 31, 2001, that such a study would be, “logistically impossible to do ... No one has yet been able to come up with a protocol.”

Some have suggested doing a when-to- start study in a developing country. But in places that can barely afford HAART or the necessary infrastructure, treating people with CD4 counts over 350—or even over 200 cells/mm3—may be a luxury such countries can ill-afford, even if some so-far-undetected benefit actually accrues to such a strategy.

At the Retrovirus conference, one of the leading figures in the Adult ACTG told me that, having dismissed the idea of a randomized when-to-start study with clinical endpoints, the AACTG is now exploring the feasibility of 1) smaller, randomized when-to-start studies looking at viral load, CD4 counts, and other laboratory parameters, and 2) establishing a larger observational cohort which, supposedly, could shed light on the question.

There are several problems with this approach. The smaller randomized study with surrogate markers simply wouldn’t answer the question of whether people who start treatment earlier live longer or not. Obviously, CD4 counts would be higher, and RNA levels lower, in the group that was treated earlier. But this might not affect longer-term outcomes. A prospective observational study would be expensive, wouldn’t answer the question any sooner than a randomized controlled trial, and would suffer from all the limitations of the observational studies described above.

It appears unlikely that any of the NIH-funded trials networks will do a controlled clinical endpoint study looking at when to start. It appears even less likely that such a study could be carried out in resource-poor developing country settings. Perhaps the Europeans, in conjunction with other developed countries such as Canada or Australia, may do such a study—but clinicians in those countries already tend to start treatment later.

More likely, we’ll have to continue to rely on observational studies with accumulating inferences, hints and clues from smaller randomized studies, as well as new and emerging insights about predictors and correlates of various drug-related adverse events, to guide the standard of care for the next few years.