On a Darkling Plain -- The Years of Despair

And we are here as on a darkling plain
Swept with confused alarms of struggle and flight,
Where ignorant armies clash by night.

-- Matthew Arnold, "Dover Beach"¹

This is the second in a series looking back at the first two decades of TAG's work to speed up AIDS research. In Part I: TAG's early campaigns to reform the National Institutes of Health (NIH) AIDS research, boost the federal budget, and revitalize HIV basic science research.² Here we look at the clinical science of AIDS before the discovery of highly active antiretroviral therapy (HAART) in 1995-96, and how TAG responded to the needs of people with AIDS.

For most of the early 1990s, it seemed that the science of HIV treatment was going backwards. In 1987, AZT became the first Food and Drug Administration- (FDA-) approved AIDS drug, giving hope to researchers and people with AIDS alike that this seemingly untreatable virus could be tamed. The NIH auctioned off two AZT-like drugs, ddI and ddC, to drug companies for development. In 1991, ddI (Bristol-Myers Squibb's didanosine) was approved based on changes in a surrogate marker -- a small rise in CD4 T cells in people receiving ddI, versus a continued decline among those on AZT -- before the study's final results demonstrated whether the CD4 cell increase predicted actual clinical benefit.

Early in 1992, the FDA formally issued regulations for accelerated approval to allow marketing of a drug for AIDS and other serious or life-threatening diseases based on such early changes in surrogate markers. It seemed like a great victory for the AIDS activists who had long struggled for such regulatory reform.

In April 1992, Hoffmann-La Roche submitted a new drug application (NDA) for accelerated approval of ddC (zalcitabine). I was an ad hoc community representative for the FDA Antiviral Drugs Advisory Committee hearing. It was not a pleasant task. The data on ddC were difficult to interpret. The drug had serious side effects including potentially crippling nerve pain. But a strong consensus for approval emerged among the AIDS activists at the hearing. I voted to approve ddC -- not because it looked effective, but because of the desperate need for new treatments. A closely divided FDA advisory committee recommended a narrowapproval.

The benefits of these drugs were short-lived in the case of ddI, and nonexistent with ddC.

The difficulties of HIV treatment research in the early 1990s could be summarized as a vicious cycle caused by a combination of bad drugs, badly designed clinical trials, and inadequate measures or markers of anti-HIV drug activity.

Bad Drugs

First, the drugs. Virtually all the drugs under study in the early 1990s -- ddI, ddC, as well as the subsequently approved d4T (stavudine, 1994) and 3TC (lamivudine, 1995) -- were nucleoside reverse transcriptase inhibitors (RTIs). The nucleosides block the HIV protein reverse transcriptase from turning viral RNA into DNA by prematurely terminating the DNA chain, making it impossible for the virus to fully replicate. They differed, however, in their potency (anti-HIV activity), duration of effect, as well as in their toxicity.

AZT attacked the bone marrow, causing anemia. DdI, ddC, and d4T caused serious nerve damage, and sometimes pancreatitis. 3TC appeared the most benign of the first five nucleoside RTIs approved by FDA, but it was also the last to market.

By themselves, none of the nucleosides worked for very long against HIV. According to National Cancer Institute (NCI) virologist John Coffin, these drugs, used singly, caused "little" virus suppression. His measurements were based on viral RNA measurements -- so-called viral load tests -- which were not yet available in the early 1990s to most researchers, let alone to doctors and patients.

Badly Designed Clinical Trials

According to the well-known dogma of combination therapy for difficult-to-treat infections -- when studies in the 1950s for tuberculosis made it possible for the first time to cure the disease -- it is necessary to use two or more active agents against an organism that rapidly develops resistance to one drug used alone. As early as 1989, when ACT UP's Peter Staley and I met with chain-smoking Burroughs-Wellcome virologist and AZT supremo David Barry at Research Triangle Park, North Carolina, he told us that the future of HIV treatment lay in combination therapy.

The federally funded researchers at the NIH's AIDS Clinical Trials Group (ACTG) knew this. But most of them had worked only on herpes, a virus against which a single drug -- acyclovir, discovered and brought to market in the early 1980s -- worked for most people.

The ACTG's early attempts at anti-HIV combination therapy would have been laughable had they not resulted in so many failed studies and wasted lives. Approaches such as one week of AZT alternating with one week of ddC were a recipe for the rapid emergence of resistance to both drugs. More often, they added a single new drug to an already-failing monotherapy. The most notorious of these studies, ACTG 155, compared AZT with ddC alone and with a combination of AZT + ddC in a group of people who had already been on -- and most likely developed resistance to -- AZT.

In spring 1993 came more bad news -- the British-French Concorde study showed that early use of AZT (taken before the onset of symptoms and when CD4 T cells were still between 200 and 500 cells/mm³) didn't provide any benefit over the longer study period.

In response, TAG intensified our work as a watchdog over the ACTG and industry studies of anti-HIV drugs, and deepened our expertise in clinical trial design, statistics, and HIV pathogenesis. We participated in and criticized the studies designed and carried out with public and private funds alike. We were members of key ACTG committees and met frequently with each company making a potential AIDS drug.

In June 1993, TAG and our colleagues witnessed the collapse of all the early hopes for combination therapy at the International AIDS Conference. As David Barr wrote for TAGline in 2003:

In Berlin, two central ideas at the heart of the treatment strategy were disproved. The first was that early use of AZT was beneficial. This was not a surprise, as the results from the Concorde study only proved what most people with AIDS on AZT found out the hard way: the drug stops working when used alone. ... The results of ACTG 155 ... showed that the two drugs did no better than one in helping people failing on AZT monotherapy. The bug was still mightier than the drug.

This was depressing enough. What made it even more depressing -- and infuriating -- was that NIAID [the National Institute of Allergy and Infectious Diseases] and the researchers involved in the study skewed their reports on the study results. Instead of presenting the results of the planned analysis, which showed the AZT+ddC combo as ineffective, an unplanned and statistically underpowered substudy analysis was performed which showed, in one of the arbitrary T-cell groupings, that patients on two drugs did "better" than the other patients. ... Margaret Fischl ... started presenting the post hoc substudy analysis, and we all lost it.

Mark Harrington, Gregg Gonsalves, Derek Link and I were all there, and we got up and just started to scream that this was a pack of lies. Dr. Fischl got all flustered. I got up from my seat and went to the microphone and started yelling that she was not telling the truth. She responded and had to admit that the planned results of the study were the exact opposite of what she was presenting. We continued to yell. The audience knew we were right and started applauding our comments. Finally, we all walked out of the auditorium.³

As I wrote at the time:

After the Berlin conference, ... [chief ACTG statistician] Steve Lagakos commented to one community member that "those activists wouldn't be so mad [about the much-hyped "subset trend analysis" from ACTG 155] if the drugs were better." Well that's right Steve! -- if the drugs were better, then the trials wouldn't need to be bigger, or better designed, or analyzed more honestly -- in fact, if the drugs were good enough, we might not need answers from randomized trials at all, as in the case of ganciclovir [DHPG]. But the drugs aren't better -- and that's why we turn to statisticians in the hope that they will help design studies competently, and analyze them honestly, keeping in mind that the primary goal is the development of information useful to patients and their providers.⁴

Indeed, in ACTG 155 it appeared that combination therapy was 50% more toxic than either monotherapy, but no more effective.