3.2 Samuel Broder: The First Clinical Trials of Antiretroviral Drugs

Samuel Broder: [00:00:00] Now I will ask a very important question in our times, forgive me in advance. Is this mic on?

[laughter]

You had to be there. I'd like to present my personal reflections, I was asked by Bruce Walker and others to give my personal reflections on the [00:00:30] initial treatment of an 'untreatable' virus, focusing on AZT, but also covering a couple of other areas. You've seen this slide or variations of this slide by other presenters. (1) In the early 1980s, we started seeing patients who presented with this, a multicentric form of Kaposi's sarcoma. In that era, I was a [00:01:00] board-certified medical oncologist and also had trained as a clinical immunologist, I had never seen any form of Kaposi's sarcoma. I had read about them, but never any form, and certainly, I had never seen this.

These are patients that presented with profound immunodeficiencies, sometimes exclusively in that state, but also with Kaposi's sarcoma multicentric. You can see the patient has edema of the flanks, [00:01:30] which was common in that—exudation of fluid was very common. These patients came and we literally did not know what to do with them. We had never seen this before, we had effectively no realistic response. I was in my mid-30s when these patients started coming to the [NIH] Clinical Center. They came, some to Tony Fauci's service, some to the National Cancer [Institute], and therefore, they ended up in my [00:02:00] hands. 

I was the head of the clinical oncology program in that era. Basically, we had—I was in my mid-30s, in ways that I cannot convey in a scientific presentation, these patients disturbed me totally. I was psychologically devastated, and I could not undertake the kind of clinical detachment that is taught in medical school. [00:02:30]

The features of this disease were the Kaposi's sarcoma, which is only what I'm—Part of the story, there was also non-Hodgkin’s lymphoma (NHL), central nervous system lymphomas, patients sometimes EBV-positive (Epstein-Barr virus) lymphomas and sometimes not.

At any rate, this is a patient who presented on one of the protocols in 1983, and a protocol that started in 1992, the test combination chemotherapy, and in effect, within months, developed this florid Kaposi's sarcoma [00:03:00] and died. (2) I'm using it as a representation of the kind of problems that we faced. The median survival on our services, at any rate, was much less than a year, and essentially was probably estimated at six months at best, and sometimes patients died within weeks of an admission.

You've heard the unbelievably brilliant work from Dr. [Robert C.] Gallo and Professor [Françoise] Barré-Sinoussi [00:03:30] on the discovery of the pathogenic retrovirus, which we now call HIV. That was a source, a correct source, in my view, of universal celebration. Unbelievable achievement. Except: after thinking about it a little bit, I was not out of the soup as a clinical investigator because the pathogenic [00:04:00] organism, the causative agent was a retrovirus, and the cognoscenti of the time believed that retroviruses were inherently untreatable.

This created effectively a kind of additional dilemma and a kind of—perhaps we can retrospectively call it a false hopelessness, a term that was coined by Martin Delaney (1945–2009, founder of Project Inform), who I still remember to this day, and he characterized [00:04:30] the sentiment of that era as a false hopelessness in which people believed nothing could be done, or indeed, that anything one would do would harm patients.

Yes, there was important work related to Pneumocystis or other opportunistic infection prophylaxes, and yes, there was some modicum of progress for Kaposi's sarcoma, but in my view, we really were not making the fundamental advances that we needed to make. 

Here are some of the issues [00:05:00] that arose at that time. The high rate of viral mutation, fostering drug resistance, or coupled to proviral integration into host DNA, latent [viral] reservoirs, all of these would work against the possibility of treating this virus effectively. There was a belief by some that the clinical disease cannot be reversed no matter what, that is, the damages done and you can't reverse it.

Probably analogous, if you allow me a metaphor, to the notion that if I subject somebody to radiation, a lethal dose of radiation, it's too late to put on the [00:05:30] lead apron. The damage is done. There was the unacceptable short-term and long-term toxicity. There were abiding controversies related to the retroviral causation of the disease, and initially, no reliable animal models. Bob covered some of this in his presentation, but I learned it firsthand, that what scientists might say can turn into matters of life and death.

I'm not trying to be melodramatic, although I may sound that way, but the opposition [00:06:00] to the causation, [which was] elegantly proven on both sides of the Atlantic, in my view, had very significant consequences not only for these programs, but across the board. There [was a] belief that there would be special challenges for material-resource poor nations. In other words, maybe you'll make a little bit of progress in United States or Western Europe, but you would not affect the places in the world where AIDS was running [00:06:30] rampant beyond the proportions that we were then seeing in the US.

There was a significant failure rate of preclinical drug programs targeting any major disease. I think that maybe John Martin will get into this, but virtually any pharmaceutical program that starts out in a pre-clinical contest is going to fail, statistically. I don't make the rules. Anybody in the pharmaceutical industry knows that [00:07:00] most things at that pre-clinical level fail. You have to keep working at it, get up, dust yourself off, and keep going. In the context of AIDS, no one could assess the odds of success for this unprecedented disease, and that added an extra complication.

There were also other issues that arose that I will tell you as I went through this in a retrospective kind of way. There was consequences to my lab personally after [00:07:30] we started to get into this. By the way, I viewed what my lab was doing as practicing medicine by other means. I do not hold myself out as a scientist on the level of the brilliance of a Gallo or Barré-Sinoussi. I was practicing medicine in the [NIH] Clinical Centre, although I had a lab to do it, and then could move from the clinic to the lab and back again in one continuous motion, if necessary, but primarily, my interest was as a doctor.

[00:08:00] I did my internship with Doug Richman at Stanford University Hospital. Everything I know about medicine, he taught me, but he taught me that things are really hard to do, and you have to focus. I came up, and I was not alone, with a hypothesis which is ridiculously simplistic in today's world. You will probably scoff at what I'm about to say, truly scoff [00:08:30]. If HIV replication is blocked by a targeted therapy, the virus probably can't do damage, or at least any further damage, focusing only on the short-term given the dire acute prognosis. I am fully aware that a retrovirus can continue to produce proteins that are toxic in some way, or continue in some sanctuary site or some provirally integrated site, produce a viral product that induces a chronic inflammatory state.

In this era, we didn't have the luxury of worrying about chronic [00:09:00] anything. These patients died quickly, at least in the ones that were being referred to us. That was the hypothesis, block viral replication, and you're probably going to benefit the patient to some extent. Now, although no one in the room today who was in that era will stand up and say, "Of course, we did not oppose that." Please—many in effect did.

There were some exceptions, the Gallo group was an exception. Ironically, as you already heard from Marty St. Clair, there was [00:09:30] essentially one company that also believed this point of view. That was the Burroughs Wellcome Company. Now, most of my contacts—and when I say I'm interacting with the Burroughs Wellcome Company later on in this presentation, if I forget to say it, virtually all of my interactions were with Dave Barry (1944–2002), an exceptionally brilliant scientist who would certainly be at this symposium, but of course, he died early in life.

[00:10:00] There was an issue, however, for me. That is, in any event, I was not prepared to advance any new agent into my clinic without first documenting an antiretroviral effect and a therapeutic window in vitro against HIV per se. This would especially apply to a first-ever use of a new chain-terminating nucleoside in AIDS patients.

Now, it is easy in retrospect to say, "What's the big deal?" but chain-terminating nucleosides [00:10:30] were a big deal in that era. This was an issue for me, and a nontrivial one. For example, there are barriers to using an experimental nucleoside analogue in this setting, in the setting of AIDS. There are barriers that are not theoretical. For example in a phase 1 trial of fludarabine, another nucleoside, not related in an immediate sense to AZT, but a nucleoside or nucleotide, nevertheless. (3) In 1984—[00:11:00] this was a phase 1 study in cancer patients, but the point still will hold—total T cell counts fell during all treatment courses, with the mean absolute T-cell count decreasing by 90%, and there was a reversal of the circulating T4:T8 ratio.

You think about a chain-terminating nucleoside which has never been given to human beings in any essential sense of that term, which is, therefore, even though not a new drug—[00:11:30] not an old drug but a new drug nevertheless—and you think about what it means to take that into a patient with AIDS for the first time, which we did. We introduced the drug to human beings with AIDS for the first time in the Clinical Centre under my direct supervision, the first patients. The fear that I had at the time was at any point, we would harm the patients, and so before we agreed to go into people, we had to make sure that we had to set up our own categorization, our own gating function [00:12:00]. 

This is the first paper describing AZT as a potential agent targeting HIV-1. (4) The first author is Hiroaki Mitsuya (b. 1950, 満屋 裕明), who was in that era a fellow in my laboratory. This was the so-called Mitch Mitsuya before he became famous. Nevertheless, he was in my laboratory performing experiments under my supervision. This was a collaboration involving Duke University and the Burroughs Wellcome Company. In effect—Here is moi [00:12:30] [chuckles], we used this paper. Yes, it was a wonderful publication, but the work that went into this publication was used as the gating function for whether we could go into human beings. That is where the decision point was being made. 

Now, this is one kind of study from that paper, and there was others that we did that were not published. What you see is that these are various doses of AZT, and in effect, we used them against immortal clones shown [00:13:00] on the right panel. You can see that with our drug, the black bar shows you a destruction of the population, but you can protect the population of target cells with doses of AZT that would be achievable in human beings.

We were not satisfied with that, and in the case of AZT, we actually developed a normal clone of tetanus-toxoid-specific helper-inducer T-cells that would respond to tetanus toxoid. It was very important for us to learn whether AZT would destroy that population [00:13:30] or damage it in some fundamental way. 

We didn't have animal models, we didn't have a humanized mouse, and we couldn't wait. You don't know what we didn't have. We didn't have PCR—real-time PCR. We didn't have whole genome sequencing and assembly, we didn't have the internet, we didn't have Facebook. Maybe we were slightly better off in some ways, but we didn't have anything. I would not be able to use PowerPoints to give you my presentation in that era.

This is a course aspect of what we did. Many people have chosen to go this route by [00:14:00] some manner or means. Just take a cell line and put a drug in and look for p24 (HIV capsid protein) expression or what have you, or look for cell death or cytopathic effect. In my view, that was not sufficient. It would not be sufficient for me, because I was going to administer, or people under my direct supervision were going to administer a chain-terminating nucleoside to human beings with AIDS for the first time, it could have gone wrong.

These are some of the data that came from that paper, I won't go through it. For those who might be interested, the paper is on [00:14:30] the order of magnitude of well over 30 years old, so I'm not going to—I'm just going to give you the basic conclusions. P24 could be blocked. The helper story I showed you already. There was a Haitian isolate that was kindly provided by Bob Gallo and his co-workers. It was highly divergent from other forms of HIV, and it too was suppressed by AZT.

We found there was a reverse transcriptase inhibition in peripheral blood mononuclear cells (PBMCs). [00:15:00] This was an experiment done by Kent [J.] Weinhold, but all the other experiments here were done in my laboratory. One of the most important was, a therapeutic window, we used tetanus-toxoid-specific T cell clone activation, and we showed that against specific tetanus toxoid responses, PHA (phytohemagglutinin) and ConA (concanavalin A) helper [T cell] function for immunoglobulin had mere survival over approximately overall two weeks. We felt that there would be a sufficient window, if you will, a safety margin.

[00:15:30] We have AZT, and I'm going to give you the clinical things in a moment. I'm saving the good stuff. But, in addition, a central question emerged early: Is AZT alone? Is there some peculiar property of AZT? Is it the azido group? Is there something we don't understand? Is it a black box, or is this going to be the end of the line, or are there other drugs that are likely to come along? Because it makes a difference as to how you think about it and how I ask for resources.

By the way, [00:16:00] from much of the early work I did in this setting, we did not have extra funding. Everything was essentially reprogrammed. There were people in the cancer community that felt we should be doing nothing against the causation of AIDS, that we should be doing 'cancer', and some of them were influential. As I mentioned, there were issues in my laboratory that, briefly but significantly, almost brought it to a halt.

[00:16:30] We needed to find out, was there anything else that was going on? Were there other drugs? In the literature, there were reasons for believing other drugs would work? And sure enough, we were able to show that it was a dideoxy configuration of the ribose that was very important, and you were likely going to get other drugs. (5) There was other things you could do to be sure, but we felt other drugs would easily come up in some manner or means.

Here's dideoxyadenosine (ddI, Videx), which is just one example, it worked. But other things did not work. [00:17:00] Cordycepin (3'-deoxyadenosine) did not work. ARA-A (vidarabine, 9-β-D-arabinofuranosyladenine), which in the literature was supposed to work against murine retroviruses did not work. 2',3',5'-trideoxyadenosine did not work. So we had a strong belief that there was some rationale for thinking other products would be available. 

This was the first clinical trial, the phase 1 study that showed activity against effectively the cause—the manifestations of [00:17:30] AIDS. (6, 7) Bob Yarchoan was the clinician of my group, and there's yours truly. This was another collaboration that involved the Burroughs Wellcome Company, Duke University, Margaret Fischl is on here, and it does bring in a wonderful representation from [The University of] Miami. I will say if Margaret in the audience, will you raise your hand? Pity, because Margaret is a wonderful person, was a wonderful person in that era, and had the kind of attitude to [00:18:00] calmly reassure everyone including me when we were in a sense of, nothing is going to work, [chuckles] kind of deal. 

We found that the drug was orally bioavailable. All of the clinical pharmacology in this study was done at the National Cancer Institute. We found the drug had a bioavailability of over 60%. We also found that it penetrated the CNS (central nervous system), which was all good.

Here are now the series of clinical events, and I'm going to describe them very quickly. This is the very first patient who received AZT [00:18:30]. The patient converted from anergy (a lack of immune response) to a positive PPD. So it's still an uncontrolled study, but then people ask me, how did I really know things were working? It may surprise you. I internally knew that this drug was working because of its effects on the CNS. I'm not making that up. Here's an example. We published a paper early in 1987 to summarise some results. (8) Here's a normal glucose uptake metabolism of the brain on a [00:19:00] PET scan. Here's a patient before and after AZT. You do not have to be a nuclear medicine expert to see the glucose metabolism, the level of brain functioning is restored.

Here’s another patient, three segments, before and after. (9, 10) The brain is lighting up, but in addition, we were seeing functional improvement, cognitive improvement at the bedside and with appropriate IQ tests. Here's another patient before and after.

Now, I want [00:19:30] us to talk about Sandy Lehrman for a minute. Sandy did something very important in our group, and basically, more or less, was quite an advocate for trying pediatric patients and enrolling them quickly. As it happened, ironically, to me personally, not to the rest of the world, some of the most convincing effects we had on AZT were in children, ironically. So here's another example. Basically, this was a child, an 11-year-old patient who acquired [00:20:00] AIDS by virtue of a concentrated hemophilia factor VIII reconstruction. (11) Basically, this is the patient before and the patient afterwards. This patient had an IQ of 99 measured through school testing before he became symptomatic. He dropped to 71, an IQ of 71 when he was symptomatic, and after AZT, his IQ improved back the 99. (Philip A.) Pizzo and coworkers right down the hall from me, [00:20:30] showed a mean improvement of IQ of 15 points. That's serious improvement for a child.

While the rest of the world in effect—and I'm not trying to be whining, although it will come out that way—the rest of the world was asking me, "Why are you saying AZT works?" I was watching results like this, and that is why I knew that AZT was working. What we thought we learned from AZT was it's an active agent with clinical benefit, [00:21:00] with immunologic improvement, and surprisingly, neurological features that improved. We learned that the drug had significant side effects, especially hematologic toxicity. We also knew that AZT was not a cure. There were patients who got better and then got worse, and we made that point clear to people.

The data from the Phase 1 study did not and realistically could not prove that AZT increases the survival of patients, and could not change the beliefs of thought leaders that informed the practice of medicine. Phase 1 studies just [00:21:30] can't. They can be affected by ascertainment bias, regression to the mean, and everything. I knew that.

Dave Barry and Dannie King, who I believe—has Dannie King been mentioned at this symposium at all? Then you can't say that anymore. He has been mentioned—Dave Barry and Dannie King, both, got together and effectively organized the history-making AZT collaboration, which was done—I will embarrass the people in the audience—by the finest clinical trialists and investigators in [00:22:00] the world. Doug Richman was one of them, Margaret Fischl was other, but I'm not—if I leave somebody out, forgive me.

This was an unbelievably important study, and it showed that AZT can decrease mortality and the frequency of opportunistic infections in a selected group of patients. (12) That patients receiving the drug, particularly those with AIDS, showed improved cognition. (13) And the drug exhibited serious hematologic toxicity. (14) I take this as a confirmation of our studies. The fact that [00:22:30] this study at all was done is an astonishing thing, but I also want to mention that the criticism that we heard of it is valid. You normally would not go into a randomized phase 2 at a fixed dose that you pick without doing a lot more trials, a lot more dose-seeking studies.

As with all human endeavors, this perhaps could have been done better, could have been done differently, but it was done and it proved a lot of points.  Now, that [00:23:00] was the good news. 

I'm going to give you a reality check. AZT was approved on March 19th, 1987. The sponsor was Burroughs Wellcome. That name has passed to history, as you heard. ddI, another drug for my lab, based on the paper I showed you earlier, was not approved for greater than four years later, October of '91. ddC (2’-3’-dideoxycytidine, Zalcitabine) another drug from my lab, was not approved until June 1992. d4T (stavudine, Zerit), which [00:23:30] originated from Ray Schinazi and others, it was not approved until seven years later, and the sponsor was a Bristol-Myers Squibb. 3TC (lamivudine) was approved eight years later on November 17th, 1995. These are from the FDA website.

In other words, it took a long time to come up with other drugs. It took a really long time, and we maybe need to examine why that is. Even Burroughs Wellcome did not [00:24:00] develop another agent by FDA approval for approximately eight years. I looked at the audience and there are some young people in the audience. By the way, my definition of young is that you're under 70, but there are people that are even younger than that. I want you all to know, this is the world that I lived in, and most of the people that are over a certain age lived in. This is the death rate for people who have fulminant AIDS—[00:24:30], not early HIV infection, fulminant AIDS. AZT was approved in 1987, the death rate per year was close to 400 deaths per 1,000 persons, and this is the world that you live in. You live here.

Do we need to do more? Absolutely, we need to do more. And it took too long. But this is an astonishing development for an untreatable disease. This is my lab at its peak. At one [00:25:00] point, the lab was Hiroaki Mitsuya and me working on these projects. One person who wasn't in the picture is Jan Balzarini, I just want to mention him quickly, and Erik De Clercq (b. 1941, Belgian biomedical researcher). I called Erik De Clercq in 1984 and had the—I cheekily offered him a chance to come to my lab. In retrospect, it was a ridiculous invitation—but to come to my lab to help us out. He patiently did not call me [00:25:30] an idiot, and basically did something very gracious. He sent what in retrospect was his best fellow, Jan Balzarini.

This is from the memoir that he did and published in 2015. (15) He sent him “for a year to work in Sam Broder's laboratory”—that would be me—“on the anti-HIV activity of new nucleoside analogues.” Jan got—effectively came almost immediately or close to immediately right after that for a short stay [00:26:00], and then came back for a full year later in 1985, and was an astonishingly productive person. He went back home and worked with Erik and did some phenomenal work on the acyclic nucleoside phosphonates, which are some of the most important drugs ever developed in AIDS therapy. (16) You might hear more about them from John Martin. But I want to say one thing that this slide proves, is, despite my mentorship, he rose to a high length in science.

[laughter]

[00:26:30] Normally, we speak about the future, so here's a future that I probably will have no immediate role in, but I personally believe that AIDS will be cured in my lifetime. The joke will be, I'll have to live a few extra years beyond my normal span, but I believe it will be cured in my lifetime. I believe there are data now that a true cure, by which I mean: excision of the retroviral provirus from the [00:27:00] body, the ability no longer to require antiretroviral therapy, the non-detectability of the virus throughout the person's lifetime, and an actuarial equivalent survival to an age match control. (17) That's my operational definition of cure. I believe that will be achieved.

I think that the methods of using gene editing using a short version of Cas9 endonuclease together with a multiplex of guide RNAs with a [00:27:30] rAAV9 vector, has already been shown in transgenic animals to essentially remove the virus as I've described, so I personally think a cure for the disease is possible. Many of you may know that I was recently for a company called Intrexon, which has a gene switch technology, and I also believe that that gene switch technology can be applied to other things such as chimeric antigen receptor T cells and so on. [00:28:00]

I want to thank you for the privilege of being here today.

[applause] 

John Mellors (Moderator): We have time for a couple of questions. Robin?

Robin Weiss: Would you like to say a word about the evolution of resistance, when you first observed it? [crosstalk]

Sam Broder: The question was, when did we—Do you mind if I repeat the question?

Robin: Yes, go ahead.

Samuel Broder: When [00:28:30] did we observe resistance? I think Doug Richman is going to talk about that more, but ironically, on a clinical basis, we observed it in our phase 1 trial. There were a series of patients who got better, and a couple of them within weeks of getting better, and by better, I mean their CD4 counts went up, and they gained weight, and they felt good. Even some of them had neurologic improvements, ironically reverted, lost everything.

[00:29:00] We construed that probably—I think it's interpreted, but rather, we'll say we considered it to mean that we were seeing clinical resistance to a single agent. It was never our intent that we would go with a single agent. That's why those studies I showed you about other dideoxies was so incredibly important. Not that we were going to discover other things necessarily, but we just wanted to make sure this wasn't the only thing that we would ever deal with. By the way, we made it clear as early as we could, AZT was not a cure for AIDS. 

John: [00:29:30] Larry?

Larry Corey: Yes. I guess I want to maybe add a little local color, that I think—Because I was at that time the darling of aciclovir, I had an enormous amount of contact with David [Barry] and Dannie King, and Trudy (Gertrude B. Elion, 1918–1999) who was one of my mentors. I would say that they had a lot more optimism than you projected from the podium about—

Sam Broder: [00:30:00] Who had—I'm sorry, I'm missing what you're saying.

Larry: I would say that they had a lot more optimism about the safety and the efficacy of the drug.

Samuel Broder: Who's the "they"? What's the antecedent to the pronoun?

Larry: The antecedent is Trudy, David, and Dannie. That's the antecedent. They felt very—Especially Trudy, they felt very confident that they had gotten far enough that this was a viral-specific enzyme, [00:30:30] that they were going to have some effect. What the relative ratio of—toxic to therapeutic ratio would be, they obviously didn't know, and that needed to be worked out clinically, but there wasn't any real hesitation at all, I don't think, from the company at all. I think the aciclovir success, the fact that they had follow-up drugs with aciclovir and now they were moving into a new era that the precedent would hold. I just wanted to say [00:31:00] that I think that there wasn't a lot of pessimism about what would happen.

Sam Broder: All I could do is speak for myself. I think you can go through my bibliography if you have—If you don't have a life and have nothing else to do, you could go through my bibliography and you probably will not find unwarranted, unmodified—Sometimes optimism, for sure, but we normally had quite a bit of modification [00:31:30], and warnings, and cautionary notes, and all sorts of things at the time. It's a double-edged sword. There was no question that this drug was working, at least in certain settings. That's the astonishing thing to me, not that-- You always have to be careful about becoming overly enthusiastic. I take your point and I thank you for making it, but this drug was working.

Somebody accused [00:32:00] me of being a cheerleader for AZT, or maybe meant it as a compliment. I think it was the former, but it was a funny situation for me. My colleagues were cautioning me to not go overboard and were teaching me as though I needed to learn the dangers of concluding things from Phase 1 studies in that era. I understood that totally, but I had no other explanation for—[00:32:30] especially, the pediatric studies and the CNS studies in adults. They were sterling and perhaps unanticipated by most people, so something was working. Was it the end of the line? No, but I think the thing to take away from AZT was not that AZT, per se, meant that much.

I don't wish to necessarily get into the issue of whether the Phase 2 study should have been done or not, that we can obviously—people of [00:33:00] goodwill can discuss that. I personally think Dave Barry was an astonishingly advanced thinker, but maybe he was—we can talk about that. All I know is that we were seeing internally, admittedly in uncontrolled circumstances, results that, I can tell you, my colleagues did not believe. Literally did not believe. I felt that, [00:33:30] "Well, I'm seeing these results. I don't think we're making them up." That part was a little bit of a disconnect for me personally because the drug was working in my hands, I thought.

The possibility that anything would work against a retroviral disease of this magnitude, of this gravity, of this dire consequence was, to me, a really astonishing event. Maybe all of us didn't choose [00:34:00] to balance that with the realities of the moment.

John Mellors: I'm afraid we're going to have to move on. Thank you for your passion and your conviction.

[applause]

Samuel Broder: That's a compliment?

John Mellors: It is a compliment. I'm going to pay you another compliment. My brother-in-law was very, very ill from AIDS. He was a Pan Am flight attendant, and he was rejected from the suramin trial being conducted [00:34:30] at NIAID. In desperation, I called the Broder lab and you picked up the phone. You said, "Forget about suramin, it's toxic." You were very excited because you had just learned from Mitch that BW[A]-509U 81 (AZT) was active against HIV, and you said, "Your brother in law should get on this drug." Unfortunately, [00:35:00] he didn't make it, but I really, really appreciated that at the time.

Samuel Broder: Thank you for that. I appreciate it.

Moderator: Yes.

[applause]

[00:35:13] [END OF AUDIO]

Citations 

1. Broder, Samuel. “The Development of Antiretroviral Therapy and Its Impact on the HIV-1/AIDS Pandemic.” Antiviral Research, Twenty-five Years of Antiretroviral Drug Development: Progress and Prospects, 85, no. 1 (January 1, 2010): 1–18. doi:10.1016/j.antiviral.2009.10.002.
2. Gelmann, Edward P., Dan Longo, H. Clifford Lane, Anthony S. Fauci, Henry Masur, Margaret Wesley, Olivia T. Preble, Joan Jacob, and Ron Steis. “Combination Chemotherapy of Disseminated Kaposi’s Sarcoma in Patients with the Acquired Immune Deficiency Syndrome.” The American Journal of Medicine 82, no. 3 (March 1, 1987): 456–62. doi:10.1016/0002-9343(87)90445-1.
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Index 

• 1.4 Robin Weiss — Retrovirus History and Early Searches for Human Retroviruses 
• 2.4 Robert "Bob" Gallo — Discoveries of Human Retrovirus, Their Linkage to Disease as Causative Agents & Preparation for the Future 
• 2.5 Françoise Barré-Sinoussi — Discovery of HIV 
• 3.1 Marty St. Clair: Discovery of AZT as the First Anti-HIV Drug 
• 3.3 Douglas Richman: Antiviral Drug Resistance and Combination ART 
• 3.4 Raymond Schinazi — Discovery and Development of Novel NRTIs 
• 3.6 John Martin — Making it Simpler: A Single Pill to Treat HIV 
• 3TC (lamivudine) 
• 6.3 Bruce Walker — Role of T Cells in Controlling HIV Infection 
• 8.1 John Mellors — MACS and Beyond: Epidemiology, Viremia and Pathogenesis 
• aciclovir (ACV) 
• analogy
• AZT (azidothymidine) 
• Balzarini, Jan 
• Barry, David Walter "Dave" (1944–2002) 
• blood — banks, donors, plasma, screening, transfusions, clotting factors (factor VIII) 
• Bristol-Myers Squibb 
• Burroughs-Wellcome & Company (GlaxoSmithKline) 
• cell culture, tissue culture, immortalized cell line 
• clinical trials (phases of clinical research) 
• Concanavalin A (ConA) 
• control — experimental control, control group, blinded experiment 
• counterfactual history 
• CRISPR-Cas9 
• cure vs. remission of HIV/AIDS
• d4T (stavudine, Zerit) 
• ddC (dideoxycytidine, zalcitabine) 
• ddI (didanosine, Videx) 
• De Clercq, Erik (b. 1941) 
• Delaney, Martin (1945–2009) 
• demographic cohort 
• drug discovery and development 
• drug resistance 
• Duke University, Duke University School of Medicine 
• early theories of AIDS etiology 
• Elion, Gertrude B. "Trudy" (1918–1999) 
• Epstein-Barr virus (EBV) 
• FDA (US Food and Drug Administration) 
• Fischl, Margaret 
• fludarabine (Fludara) 
• funding and grants 
• Haiti 
• hemophilia 
• highly active antiretroviral therapy (HAART), combination antiretroviral therapy (cART) 
• humanized mouse 
• hypothesis 
• immunology 
• in vitro vs. in vivo
• internet 
• Intrexon Corporation  
• IQ test 
• Kaposi's sarcoma (KS) 
• King, Dannie H. 
• lab vs. clinic 
• leukemia and lymphoma 
• medical school, residency, and fellowship
• mice 
• Mitsuya, Hiroaki "Mitch" (b. 1950, 満屋 裕明) 
• models (model systems, model organisms, modeling) 
• National Cancer Institute (NCI) 
• NIH Clinical Center (NIH CC) 
• non-maleficence (primum non nocere) 
• nucleosides, nucleoside analogues, nucleoside reverse transcriptase inhibitors (NRTIs), nucs 
• objectivity 
• oncology 
• PCR (polymerase chain reaction) 
• pediatrics, pediatric AIDS 
• PET scan (positron emission tomography) 
• pharmaceutical industry 
• phytohaemagglutinin (PHA) 
• Pizzo, Philip A. 
• Pneumocystis pneumonia (PCP) 
• PowerPoint 
• provirus 
• retrovirus classification, subfamilies, and genera 
• reverse transcriptase 
• scientific controversy and consensus 
• sequencing, DNA 
• Session 3: Antiretroviral Therapy 
• Session 7: Prospects for an HIV Vaccine 
• Stanford University 
• suramin 
• United States
• University of Miami 
• viral reservoir, viral latency, disease reservoir 
• Weinhold, Kent J. 
• Yarchoan, Robert (b. 1950)