A Brief History of AZT, HIV's First 'Ray of Hope'

In 1987, a year of extra life for an HIV patient could be everything.

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Mar 21 2015, 12:00pm

​Image: Wikimedia

​1996 is usually regarded as the year HIV changed. With the development and approval of the regimen of antiretroviral drugs known as HAART (highly-active antiretroviral therapy), an HIV infection no longer meant (or means) a lingering, painful death of colluding opportunistic infections. HAART offers at least the possibility of a reasonably normal and healthy life and lifespan. And more often than not it delivers.

So: A brutal, invariably terminal condition became a chronic manageable condition, like diabetes. That in itself is one of the greater conquests of modern medicine.

1996 was a definitive year, certainly, but HAART's development began in earnest nearly a decade before, with the fast-tracked FDA approval of azidothymidine, aka AZT or Retrovir, on March 20, 1987. It marked the introduction of the first effective weapon against the virus and AIDS itself, what eventually would become a key element of the multi-drug cocktail of HAART itself. It took a mere 25 months between the drug's first laboratory demonstration and its final unveiling, one of the shortest approval cycles in pharmaceutical history. The gap consisted of a controversial single blinded trial.

AZT wasn't a new compound, however. It was born decades earlier as a cancer-targeting chemotherapy candidate, only to be resurrected by the pharmaceutical outfit Burroughs Wellcome (now GlaxoSmithKline) via the head of the National Cancer Institute, Samuel Broder. The years prior to 1987 were something of a land rush on preexisting pharmaceutical compounds, as researchers combed the shelves looking for something, anything that might do the job. People were dying, lots of them. AZT, then known as Compound S, seemed to fit the bill.

From 1981 through 1987, new HIV/AIDS cases and fatalities ​doubled roughly every year. 1987 saw 40,000 deaths and nearly 50,000 new cases. And AZT hardly swooped in to save the day; in 1991, the CDC announced that one million Americans were infected.

The AZT controversy ("controversy," perhaps) isn't flattering to anyone involved. On the one hand were/are AIDS deniers, e.g. those that claim HIV infection does not lead to AIDS. (​They're still around.) These were the loudest of the AZT trial's critics, essentially making the stock AIDS denial argument that the treatment was the actual disease not HIV, e.g. AZT was causing AIDS. Which is a shame, because the trial was worthy of some criticism.

For one thing, it was only marginally conclusive (but still significant). Early participants tended to show increases in their CD4 counts, but the improvement was often thin and those counts, indicative of immune system strength, tended to decline on the other side. But something in 1986 was also, for HIV and its victims, everything.

"Then we went to the second dose, in which I think we doubled the dose," recalled Robert Yarchoan, one of the co-developers of AZT and several other drugs found in the HAART HIV suppression cocktail, ​in an NIH history. "And six out of six patients at that dose had an increase in their CD4 cells. At a certain point, we did the statistics. And around October, we realized that we were having statistically significant increases in the CD4 cells. It was just over the level of being statistically significant. We were, at that point, very, very excited that we really had something."

The AZT Collaborative Working Group published its results in July of 1987 in the New England Journal of Medicine: "The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex." The conclusion: "These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS–related complex, at least over the 8 to 24 weeks of observation in this study."

Much of the controversy surrounding the early days of AZT had to do with its dosages. Patients were being given the stuff in 1,500 mg hits and, as it turned out, AZT can be toxic. In particular, it goes after bone marrow cells, potentially leading to anemia. This was ​found to be reversible, in part, with administration of a hormone known as EPO. Meanwhile, it turns out that only a little bit of AZT will do the job. Now, a dose is more likely to be 300 mg.

The way the drug works is by targeting HIV's reverse transcriptase, the enzyme the virus uses to copy its RNA onto DNA. The result of this copying is double-stranded DNA, which the virus needs in order to integrate itself into a host immune cell. Limit this enzyme and we should expect to see the HIV infection slowing down. The catch is that, at very high doses, AZT limits the polymerase needed by healthy human cells for cellular division. The drug has a 100-to-1 affinity for HIV over human cells—HIV have less of an innate ability to repair damaged DNA—but the danger is real.

AZT could offer about a year of prolonged life in those early days.

AZT also proved to be vulnerable to resistance, exceptionally so. As Yarchoan noted, the phenomenon may have even been seen in the first patient the drug was tested on, as after eight weeks of steady improvement, their CD4 counts again began to fall.

Basically, HIV is prone to mutations within its reverse transcriptase, which, in the presence of prolonged administrations of AZT, means it's more likely to hit on a quality AZT-resistant mutation. HIV also replicates fast and HIV particles have very short lives. In a sense, the virus is constantly experimenting, evolving in fast-motion.

AZT could offer about a year of prolonged life in those early days. Which, after a decade of bleak, dark nothing, was something to behold. Even at the highest and most dangerous doses, it doesn't beat back the virus completely. HIV was still more or less a death sentence until 1996 and the development of HAART, though in the intervening years there were many attempts at improving on AZT, mostly unsuccessful.

The coup of the HAART regimen was in offering a complement to the effects of AZT in the form of several classes of drugs that block the virus's genetic replication. In addition to limiting viral loads, this limits HIV's ability to morph into more resistant forms. Resistance still happens, but the HAART cocktail is diverse and still growing. Several new compounds have been unveiled just within the past year, while, generally, required doses are going down—needing administration daily rather than several times a day—and side effects with them.

AZT itself went off of patent in 2005, and several generic forms of the drug have been approved since, making it a rarity in the HIV treatment world. On introduction, a full year of the stuff cost $10,000. By 1998, the price had only gone down to around $8,000 per year (see: ​"HIV's Inhuman Cost"), despite the influx of new, effective drugs. Currently, the lifetime treatment cost of an HIV infection is $379,668, according to the CDC.

It's a situation pretty much built to resist the generic drug market (e.g. a constant influx of novel drugs) and in 2007 the government of Brazil even went to the point of breaking international law by violating a Merck and Co. patent (issuing a "compulsory license") and ​producing its own generic versions of the drug efavirenz. Which is enough of a statement in itself.