On a Darkling Plain -- The Years of Despair
Before the Discovery of HAART
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.
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
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:
Indeed, in ACTG 155 it appeared that combination therapy was 50% more toxic than either monotherapy, but no more effective.
This article was provided by Treatment Action Group. It is a part of the publication TAGline.
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