Most progress in medical research on a disease is usually slow and incremental, and there are few eureka moments. The discovery of HIV as the cause of AIDS was one of those moments. It opened up the gates for all the subsequent studies on the disease. In contrast, much of the understanding of how the virus destroys the immune system of the body was incremental. This was true of the work that Cliff, my team, and I were doing in my lab and a growing number of scientists were doing in laboratories in the United States and throughout the world. It was during those early years that we only gradually began to understand the resiliency and destructive capability of HIV. But despite our growing knowledge of the disease, our patients were still suffering and dying at an alarming rate.
It was the mid-1980s, and we still had no effective therapy. Because of the desperate nature of the situation, people with HIV were willing to self-administer almost any substance or compound that showed even the slightest hint or rumor of being able to suppress the virus in a test tube. Searching for an effective treatment, patients were traveling to foreign countries to obtain drugs that were unavailable in their own country. One of the most celebrated examples was when Rock Hudson, who had advanced-stage AIDS, went to France in July 1985 to receive the experimental drug HPA-23, developed by scientists at the Institut Pasteur in Paris. In a later multicenter study that included our team at the NIH Clinical Center, HPA-23 proved to be ineffective in treating HIV infection. Rock Hudson died of AIDS on October 2, 1985, at age fifty-nine.
It became clear to me almost from the start that we needed to accelerate our drug discovery efforts. Soon after I established the Division of AIDS within NIAID, we initiated the National Cooperative Drug Discovery Groups (NCDDGs) modeled after an approach initiated in 1983 by the National Cancer Institute for the development of anticancer drugs. The NCDDGs were partnerships between academic institutions and pharmaceutical companies to develop drugs for HIV infection.
We also needed a mechanism to test these drugs on people with HIV. I expected that there would be multiple drugs that would be coming through the newly stimulated pipeline over the next couple of years. It was unlikely that any single clinical unit would be able to enroll enough patients to gather sufficient data to prove the safety and efficacy of the drugs. I felt we would need a network of clinical trial units to pool all the data and get solid answers to clinical questions. By mid-1986, we awarded contracts for more than a dozen AIDS Treatment Evaluation Units (ATEUs) nationwide that formed the core of the network. Not everyone at the NIH or in research institutions throughout the country was excited about spending the money to create such a network, especially when we did not have any drugs yet to test in these units. Some scientists were even saying that we were “throwing money away.” But I knew that soon we would have more drugs than we were able to test, and so, despite the skepticism and criticism, I felt it was prudent to get the units set up quickly and ready to go. That turned out to be the correct decision as many new candidate drugs began to roll in.
The ATEUs were the forerunners of a much larger network of clinical trial sites called the AIDS Clinical Trials Group (ACTG) that over the coming years would be the vehicle where antiretroviral drugs would be tested individually and in combination for their ability to suppress the replication of HIV. The future impact of this network of clinical trial units would ultimately prove to be profound and transformative in the development of highly effective treatments for individuals with HIV.
At about the same time we were setting up the ATEUs, drug companies such as Burroughs Wellcome were examining compounds that had been developed for other diseases, particularly cancers, to determine if they might also be effective against HIV. Drs. Samuel Broder, Robert Yarchoan, and Hiroaki Mitsuya at the National Cancer Institute had developed a test to determine the ability of any compound to suppress the replication of HIV. In collaboration with scientists from Burroughs Wellcome, Broder and colleagues demonstrated that the drug azidothymidine, or AZT, had potent suppressive activity against HIV in the test tube.
Another eureka moment!
The results constituted the first real breakthrough in the treatment of people with HIV. I was excited about the test tube results, but I remained guarded because the proof of the pudding would be whether the drug worked in people.
Over a twenty-four-week period in 1986, 145 individuals with HIV received AZT, and 137 received the placebo. At the end of the study, 19 patients who received the placebo had died compared with only 1 death in the group that received AZT. Opportunistic infections such as Pneumocystis pneumonia developed in 45 subjects receiving the placebo compared with 24 subjects receiving AZT. These stunning results were published in The New England Journal of Medicine on July 23, 1987. Now I felt as if shades in a dark room had been raised and flashes of sunlight were coming through.
As word spread in the gay community, despair switched overnight to optimism. It was a period of exuberance with demand for immediate access to the drug. The problem was that the application for approval by the Food and Drug Administration was just in its beginning stages, and the drug was not yet available on the market. The question was, How could we get this potentially lifesaving drug to the desperate people who needed it immediately? At that time, the end of 1986, the number of reported cases of AIDS in the United States was approximately twenty-nine thousand. There was no precedent to get a lifesaving drug to so many people prior to official approval by the FDA.
However, in the treatment of cancer, there was a precedent to assist a limited number of patients to obtain drugs, some of which were still experimental and not yet approved by the FDA. For several years the National Cancer Institute had operated a hotline for this purpose, contracted through a company called Biospherics in Rockville, Maryland, just up the road from the main NIH campus in Bethesda. It was not too much of a stretch to apply this concept to AZT distribution. We decided that NIAID would pay Biospherics to set up a twenty-four-hours-a-day, seven-days-a-week hotline for the distribution of AZT under the FDA’s “Investigational New Drug” mechanism.
Because the supply was limited at that time, we had to determine who would get the drug first. We decided that patients had to currently have or have had at one time Pneumocystis pneumonia as an entry criterion to the program. We estimated that this made as many as six thousand people eligible to receive AZT in the United States.
The key to implementing this program was Deborah Katz, a nurse employee of the National Cancer Institute who was assigned to the Biospherics contract. Debbie marshaled her friends and neighbors to staff the hotline, accepting applications around the clock. The applications had to be made by a physician on behalf of a specific patient. Every night, one of our young NIAID physicians reviewed the applications that had come in that day. Then the approved applications were sent to Burroughs Wellcome, which shipped out the drug to a pharmacy. Approximately five thousand patients received AZT through this program from September 1986 to March 1987, at which point AZT was approved by the FDA under the name zidovudine. The hotline was discontinued. From the time Burroughs Wellcome submitted the zidovudine application to the FDA to the time of approval was three and a half months—then the quickest approval of a drug by the FDA in its history.
But the promise of AZT was short-lived.
One of the characteristics of RNA viruses, particularly those such as HIV that replicate very rapidly, is that they make mistakes in copying themselves during the replicative process. These mistakes, known as mutations, may impart various characteristics to the virus. One characteristic can be resistance to an agent meant to kill the virus, such as an antiviral drug. During the course of therapy, AZT was killing those HIV viruses that were sensitive to its killing effects, but not those viruses that had mutated to become resistant to the drug. The lesson we learned was not that AZT was ineffective. The problem was that when it was administered alone, the virus almost inevitably outsmarted the drug as a result of its uncanny ability to mutate and evade killing. The solution would have to be to use a combination of drugs. This had been done successfully in the treatment of tuberculosis and certain cancers that were resistant to single drugs alone.
When a person is treated with two or more drugs that individually are effective, the virus finds itself “boxed in” and ultimately suppressed, so long as the patient continuously takes the combination of drugs. Despite best efforts, it took four years to develop the next effective anti-HIV drug—didanosine, manufactured by Bristol Myers Squibb. The FDA approved it in October 1991. These four years were extremely frustrating to me and my colleagues. Our patients were still suffering and dying, and by that time there were more than 200,000 cases of AIDS reported in the United States.
Drug discovery was steady but slow. The following year, 1992, the third anti-HIV drug, dideoxycytidine, manufactured by Hoffmann–La Roche, was approved by the FDA; then, in 1994, stavudine, manufactured by Bristol Myers Squibb, and in 1995 lamivudine, manufactured by GlaxoSmithKline, were approved.
Unfortunately, the virus was not slow. By the end of 1995 there had been more than 513,000 cases of AIDS reported in the United States. We were making considerable progress, but we were still losing the war. We were struggling with the balance between efficacy and drug toxicity. In other words, the drugs were prolonging life in many patients but not suppressing the virus completely, which was continuing to contribute to the deterioration of the patients’ condition. Meanwhile drug side effects often took their toll. In some respects, this was similar to the toxicity that cancer patients experience with chemotherapy aimed at destroying their cancer.
We needed better drugs.
In the meantime, we got much better at the art of taking care of patients with HIV apart from treating HIV itself. The practice of HIV medicine was becoming a discrete subspecialty of internal medicine and a sub-subspecialty of infectious diseases. One area of infectious disease practice that was significantly altered because of the AIDS experience was the concept of prophylaxis, or treatment of patients with a variety of antimicrobial drugs to prevent the onset of infections that frequently occurred in individuals with HIV whose immune function was severely compromised. Instead of waiting for patients to get these opportunistic infections, we preemptively treated them to prevent disease. It was the wide implementation of this practice for diseases such as Pneumocystis pneumonia, cytomegalovirus disease, toxoplasmosis, and cryptococcosis that saved or prolonged countless lives before the availability of highly effective antiretroviral drugs that completely and durably suppressed HIV.