I can’t tell you the patient’s name. But I can tell you that because of what he gave, we made breakthroughs that turned the tide on HIV/AIDS.
On a gray day in January 1986, I was heading to my lab at UAB’s Lyons Harrison Research Building when I met Glenn Cobbs in the hall, on his way to the VA hospital next door. Glenn, one of my role models in ID medicine, was known for conducting medical consults on the fly in as few words as possible. Literally without breaking stride as he passed me, Glenn announced, “Hey, think a guy over there has acute seroconversion syndrome, why don’t you scope it out, O-kee?” That was it. And really, that’s all he needed to say, because we both knew that when a patient was in that initial phase of very recent infection, it gave us a unique opportunity to chronicle how the immune system evolves in response to the virus in the earliest stages.
To get from my lab to Glenn’s patient at the VA was as simple as walking across a sky bridge connecting the two buildings, a corridor that looked a lot like the one Don Adams walked down in the opening of one of my favorite 1960s television shows, Get Smart. (None of my students today was alive then; when I try to explain this to them, their eyes glaze over and they look at their iPhones.)
I introduced myself to Glenn’s patient and explained what we thought was going on and why it was so critical that we evaluate him now and each day for the next week. Once he gave informed consent to participate in our ongoing research project, I drew twenty tubes of his blood. I marked them according to our lab’s protocol, with a four-letter identifier drawn from a scrambling of the patients initials: WEAU. Back in the lab, I prepared and stored WEAU’s blood samples. In coming weeks, I would draw many more, test some immediately, and store the rest for later use.
The patient known as WEAU had been infected with HIV sometime around Thanksgiving 1985; he ultimately died of HIV-related complications in 1991. But through the blood samples he left, WEAU may have contributed more to a quarter century of HIV/AIDS research than any other single human being. WEAU’s blood helped George, Beatrice, and me establish the natural evolution of the quasi-species nature of the virus. And that was only the beginning. Based on mostly George and Beatrice’s studies, WEAU is a part of more papers in Science and Nature (two prestigious scientific journals) than any other single individual. Studies using WEAU’s blood built our lab’s reputation for the kind of quick, solid research that drug companies needed as they worked on new agents that were more potent and better tolerated than the existing drugs.
One drug company that sought us out was Merck, and our first big study with them was hatched—to my great delight—on the outskirts of Walt Disney World, a place known for magic.
Starting in the late 1980s, the pharmaceutical giant Merck had been working on a new drug, a so-called non-nucleoside reverse transcriptase inhibitor. The existing drugs such as AZT and DDI (didanosine) were all nucleosides, false building blocks of viral DNA that, when inserted in the growing DNA chain, shut down replication and blocked further propagation of the virus. The ability of the virus to go from RNA to DNA was done through this new enzyme reverse transcriptase (RT), and the non-nucleoside agents acted by attacking the RT enzyme directly.
Structurally, RT looks like a hand, and the business end of the molecule is in the cleft between the thumb and the index finger. The non-nucleoside drugs inserted themselves precisely into that cleft and blocked the ability of the virus to interact with the RNA to produce a DNA copy. Merck had spent four or five years perfecting their candidate drugs to fit very tightly and specifically into this pocket in order to shut down viral replication with very small quantities of drug.
In January 1991, I got a call from Oscar Laskin, an MD pharmacologist who worked at Merck and had collaborated with Rich Whitley, a world-renowned herpes virologist at UAB. Oscar asked me to meet with him and one of his colleagues, Emilio Emini, to discuss a possible clinical study. Orlando, Florida, was a mutually convenient meeting destination, so in late January, I flew there accompanied by Eric Hunter, an HIV virologist who was the leader of our federally backed Center for AIDS Research program at UAB.
Over dinner, Oscar and Emilio told the development history of their lead compound, L–697,661 (a set of digits I would soon know as well as my own phone number). We began discussing what a trial might look like and the potential questions we might address at a single site study—that is, a study conducted at one location by one group of investigators using a single protocol.
To continue our planning, we drove back to Oscar’s hotel, Eric and Oscar in one car and Emilio and me in the other. As Emilio and I talked about our lives in HIV medicine, I was struck by the tall, husky Italian’s constant refrain: “I hate this virus!”
Emilio had started working on HIV soon after it was discovered. After identifying a type of protease enzyme called Renin that contributed to high blood pressure, Merck had worked on anti-Renin compounds. And because HIV also had a protease gene that was critical in the ability of the virus to replicate, Emilio had hoped to use discoveries in the anti-Renin arena to create an anti-HIV compound. Up to that point, though, he had been thwarted at every turn—one more reason for his vehement mantra “I hate this virus!”
Oscar was staying at a hotel whose rooms were appointed accordingly: pictures of Daisy and Donald Duck, a bedspread with Mickey Mouse ears, a telephone shaped like Goofy. In this marvelously cartoonish setting, we outlined two concurrent HIV drug studies: one for patients with CD4 counts below 200, with or without a prior opportunistic infection; and another for patients entering treatment earlier with CD4 counts between 200 and 500. Since L–697,661 was in very early stages of development, we wanted to assess the pharmacokinetics—the amount of drug in the bloodstream at different doses, as well as the safety in terms of side effects and the drug’s ability to inhibit the virus.
Doing the study only at UAB would keep things simpler in scientific terms but was an ambitious undertaking logistically. Each study would enroll sixty patients, fifteen in an AZT control group and fifteen each in three treatment groups at different doses of the new drug. Each patient would need a prestudy evaluation, a day-of-entry visit, weekly visits for six weeks, a postvisit evaluation—in all, ten visits over ten weeks for 120 patients. Oscar gave me a slightly skeptical look and asked, “Can you guys really enroll that many patients in that period of time with that frequency of visits?”
“Give me a minute,” I said, and opened a notebook. I drew a grid charting how many patients we would see over the ten-week period. By the end of the period, the numbers were staggering: We would be seeing over 100 patients per week! I remember looking at my completed graph, then at the Goofy telephone, the Mickey Mouse bedspread, and the Daisy portrait. I said to Oscar, “No problem, we can do it”—because at that moment all I could think was, If Disney could turn swampland into parks that get 50 million visitors a year, I can handle 120 patients on a study.
Oscar looked at Emilio and said, “Okay, we can do this, but don’t mess it up. A lot is riding on this.”
On the way back to Birmingham, Eric finally asked, “So, Mike, you can do this?” I didn’t hesitate. “We don’t have a choice.” Eric thought for a moment and said, “Yes, but what’s your Plan B?” I told the truth: “Plan B is for Plan A to work.”
We couldn’t fit a study of this magnitude into the 1917 Clinic on Fifth Avenue South, so I called Claude Bennett, explained the importance of the study, and asked if we could have some additional space. When Claude’s facilities team identified an entire suite of unused clinic space in a UAB building, empty and waiting for us, we couldn’t believe our luck. I hired two new research nurses and a new data manager. We had the new research clinic operational in less than two weeks.
There weren’t enough existing patients at the 1917 Clinic to fill the study in the timeframe Oscar and Emilio set, and that worried me. But I knew that others were in touch with patients desperate for such opportunities—and that’s how I came to know Martin Delaney and Tom Blount.
A San Francisco native and a onetime Jesuit seminarian, Marty Delaney became involved in the quest for better HIV/AIDS drugs in the early 1980s when several of his friends were fighting the virus. In 1985 Marty founded an organization called Project Inform (PI) to keep patients and the affected community aware of new developments in the fight against AIDS. Though it started out locally, PI quickly became a national clearinghouse for patients desperate for information on treatments that could prolong their lives. PI offered basic information about the virus, HIV tests, where to go to get the best care in a given neighborhood or city, and what treatments were available. For the more sophisticated, Marty and his team kept abreast of the latest drugs in development, where the drugs were active in clinical trials, and how to access the drugs via companies’ compassionate use programs. When those programs weren’t available, PI helped patients form “buyers’ clubs” to purchase drugs across the border or overseas. Marty and PI laid the foundation for what became a community-based HIV research movement, helping patients argue for and gain access to promising medications in a variety of ways, including through studies like ours.
One of Marty’s close friends was Tom Blount, a tall, soft-spoken gentleman with a goatee and wire-rimmed spectacles. Tom’s family owned a prosperous construction business in Montgomery, and he certainly had the intellect and drive to lead it, had he wished to. Instead, Tom, an architect, settled in Atlanta with his longtime partner, Jim Straley, a landscape architect and graduate student. Tom has a heart bigger than Texas and is one of the most generous men I’ve ever met. In the late 1980s, when the AIDS epidemic hit Atlanta hard, Tom tested negative, Jim tested positive—and Tom set out to do everything he could to help Jim and others fight the virus.
By 1991, Tom had helped establish a buyers’ club in Atlanta called AIDS Treatment Initiatives, which had linked up with like-minded organizations in other cities, including Marty Delaney’s group in San Francisco. The clubs helped patients who couldn’t afford new medicines on the market and connected patients to the compassionate use programs that drug companies often set up prior to their product’s FDA approval for sale in the United States. When Tom invited me to speak at an Atlanta forum, word quickly spread that Birmingham’s 1917 Clinic was gaining access to new drugs that might be able to treat HIV much better than AZT or any of the existing agents.
Within days our phone lines were overwhelmed with calls, and I realized I had a different problem: We were going to have too many interested patients. We finally settled on a ratio of two outside patients allowed to enter for each one who came from the Birmingham area.
Some who applied were naïve to therapy. Others had been on AZT in the past and were failing. Among those was Tom Blount’s partner, Jim Straley. At the Atlanta forum, Tom had confided that Jim was exhausting his available options. I had urged Tom to bring Jim to Birmingham for evaluation in our new study, and Jim was one of the first people enrolled.
With the Atlanta recruits, the study quickly filled. While it was stressful to enroll all these patients and have them return to Birmingham every week for a study visit, the patients were so motivated that very few ever missed an appointment, much less a dose of medicine.
To clinicians like me, providing access to studies was a reprieve from helplessness. I’d had my fill of hand-holding, hugging sobbing mothers at the bedside, choking back my own tears. Against the darkness of death, science represented light, progress, hope. There was no better tonic for my pain than negotiating a new trial to come to our clinic, then offering spots in the study to patients desperately clinging onto life. For activists like Marty Delaney and Tom Blount, advancing access to drugs was more than a tonic; it was an urgent mission and cause. AIDS Treatment Initiatives, Project Inform, and other groups like them around the country helped legions of HIV-positive people become informed and militant about access to medications.
In addition to Jim Straley, several patients whose situations I knew well were in the L–697,661 study: Harry Wingfield, a songwriter and musician who had been fired from his job in UAB’s theater department when his HIV-positive status became known; Alan Woelhart, an artist, actor, and foundry worker whose partner was one of the clinic nurses helping us run the drug trial; and the 1917 Clinic patient code-named Pearly James. As the study went forward, Emilio or Oscar flew to Birmingham almost every week to check on our progress, underscoring the critical nature of this study to Merck’s development plans. They’d gambled that I could deliver, even though I’d never done anything like this before. It was a bit scary but mostly exhilarating to know that several years before it would be on the market, we were able to offer our patients one of the newest and most promising agents.
How promising? In the first week of therapy, as we looked at the information for all 120 patients, we saw that the amount of virus in their bloodstream dropped by anywhere from ten-to one hundredfold. Unfortunately, by week six, for the majority of them the virus had returned to the level that was present at baseline. Through this study, we discovered that this nonnucleoside agent had worked just as expected of a potent inhibitor of HIV in the first couple of weeks. But more importantly, the study also told us that when we came at the virus with only one agent at a time, the virus basically laughed at us—it quickly mutated into a form that was resistant to the drug. (Later experiments looking at the actual clonal analysis told us that resistant viruses were appearing within two days of exposure and took over the entire population of viruses within fourteen to twenty-eight days.)
The study results made our course clear: We would need a “cocktail” of multiple agents used simultaneously to successfully suppress the virus. One agent at a time wasn’t going to cut it. George and I wrote up the original draft of the study, and the team from Merck provided expert assistance in writing the manuscript with us. We submitted the article to the New England Journal of Medicine, where it was ultimately published. We finished the manuscript sitting at Beatrice’s grandmother’s dining room table, the same table where we wrote the original quasi-species paper published in Nature— our good luck table.
Weeks later, we were at the same table discussing how quickly the virus had reversed our success and spiked back up. “You know,” I said to George, “the viral replication must be pretty rapid. We really should put that into the paper.” He agreed, and the final paragraph of our paper may have been the most important:
The rapidity with which resistant viral populations were selected reflects a previously unsuspected dynamism of HIV–1 in vivo. Although there has been a growing appreciation that microbiologic latency of HIV–1 in vivo does not exist, our study suggests an even higher rate of ongoing replication … than previously appreciated.
Unfortunately, we weren’t clever enough at that moment to focus on the critical next question: “Just how rapid?”
Fast-forward to Thursday, June 11, 1992. The phone rang at my hospital desk at one o’clock in the afternoon. I remember it so clearly because events triggered by that call would change the course of AIDS medicine and my life in it.
“Hi, I’m Jeff Lifson,” said the caller, identifying himself as a scientist working at Genelabs Technologies in Redwood City, California. Jeff said a mutual colleague of ours, Rich Whitley, “told me that you had a specimen repository that had historically collected specimens from 1987 forward on a large number of patients.” I responded, “That’s correct.” Jeff then said, “I want to tell you about a new test we have that can quantitate the amount of virus in the bloodstream though PCR. Do you have a minute?” I responded, “Absolutely.”
Ever since I had heard biochemist John Sninsky’s presentation on polymerase chain reaction (PCR) at the 1987 International AIDS Conference, I had hoped we might someday use PCR to quantify the amount of virus in the bloodstream. While working in George’s lab, we had focused on several other techniques to quantitate the amount of virus (so-called p24 antigen), but we’d only achieved crude estimates of the amount of virus in the bloodstream; and the p24 antigen values were often negative in patients without symptoms of advanced infection.
At the 1987 AIDS conference, we’d been told PCR could not be used to quantitate the amount of virus in the bloodstream because the PCR technology was so sensitive that even slight variations in the multiple rounds of dilutions in the test processes might lead to wild overestimation or underestimation of the amount of virus present. On the phone, Jeff explained that an approach he and Mike Piatak developed had solved this problem. I sketched his solution with a pencil on the only writing surface available, a paper towel.
“Do you think you have some specimens that you could send us that could help us see if our approach actually works?” Jeff asked. Of course we did. I promised I’d send them by overnight mail for delivery the next morning. After we hung up, I almost sprinted down the hallway to the repository. Since I knew our patients so well, I knew which specimens were drawn from people in specific stages of infection, and which were so-called controls from people not infected with HIV. I created an intentional range of specimens, noted what I was sending, packed the specimens in dry ice, and shipped them overnight to Jeff’s California facility.
On July 2 around 10:00 a.m., Jeff called to say he was going to send me a fax with the results. This time I skipped the paper towels and grabbed a piece of graph paper on which I listed the specimen categories—negative, acute seroconversion syndrome, asymptomatic, AIDS-related complex, and AIDS—along a logarithm scale where I could plot the results from zero copies of the virus up to 10 million copies per milliliter. Then I stood by the fax machine, my anticipation building until the machine’s bell rang and the pages spilled out. I sped back to my desk with the pages, noted each result with a dot on my graph—and when I was done, what I saw took my breath away.
The patients who were not infected with HIV had no signal whatsoever. Those with acute seroconversion, like WEAU, had well over 1 million copies per milliliter. Those with advanced AIDS had somewhere between 100,000 and 1 million. But those with asymptomatic infection—who would have been completely undetectable in our tests with p24 antigen or plasma (bloodstream) virus culture—every single one of them had detectable virus, ranging from 1,000 copies to well over 100,000 copies per milliliter. The test was showing us what we’d never been able to find before.
We’ve all heard sudden realizations or inspirations called “eureka moments.” Supposedly, they were so named because ancient Greek mathematician Archimedes was so excited about an insight he got while drawing a bath that he ran into the street naked, shouting the Ancient Greek forerunner of the word eureka, which translated to, “I have found it!” I’ve been fortunate enough to be part of a few discoveries that I’d count as eureka moments. The first was being in George and Beatrice’s lab and seeing the profusion of bands on the Southern Blot test that showed the quasi-species nature of the AIDS virus. The second was this moment: Glimpsing the potential of quantitative PCR (QC-PCR) in measuring viral load, and thus in transforming HIV/AIDS treatment. And all because of Jeff Lifson’s and Mike Piatak’s groundbreaking work with the 1917 Clinic’s blood samples.
The first lesson from this new test is that we’d misunderstood how the virus worked. Previously, when we couldn’t detect p24 antigen or plasma virus in tissue culture when people were doing clinically well, we had assumed there was a latency period during which the body was able to shut viral replication down. Wrong. It never went away; we just couldn’t see it with the testing methods we had then.
Second, it demonstrated that viral replication occurs 24/7, around the clock, in somebody who is infected. This could well explain why patients’ immune systems weaken over time under the onslaught of persistent, ongoing virus replication. I likened it to the effect of waves hitting rocks on a shore. At first there is not much impact, but after years of relentless battering of the waves, the rocks inevitably erode—just as the immune system does under the onslaught of persistent viral replication.
The ability to use QC-PCR was important for another reason: It could tell us almost immediately whether or not antiretroviral therapy was working. We no longer would lose precious weeks or months to see outcomes; we could measure viral load and know, practically immediately, whether a therapy was effective and, if so, how effective.
In almost every clinical trial of cancer and the early trials of AZT and other antiviral agents, clinical endpoints were the primary metric used to determine whether or not a drug worked. In the case of AZT, the original study took patients who were fairly sick and asked the question: How much death was prevented? Chiefly because the patients were so sick, that answer often came within six months. Either the patient got worse and died or, when AZT was able to show benefit, it took six months of study with the old modes of assessing before we could tell a real difference.
With the use of QC-PCR, we could tell whether a given regimen was working in a fraction of the previous time. And within six to twenty-four weeks, we could tell if the regimen had achieved the objective of getting the virus to so-called undetectable levels, where replication was so suppressed that the virus could no longer be seen in the plasma. It was absolutely game changing.
We published the QC-PCR findings in Science in March 1993. The timing of this discovery could not have been more fortuitous. We now could measure very accurately the amount of virus in the bloodstream and directly relate it to the antiviral activity of the drugs—just at the time when the drug companies were working on a new crop of antiretroviral agents that would be more potent, as well as better tolerated. Once these companies heard that we had validated the notion of a QC-PCR technology, they would flock to Birmingham so we could test their new drugs in relatively small numbers of patients, to assess whether and to what degree the drug had activity against the virus.
Wherever a possible HIV drug breakthrough was mentioned, the press was sure to follow. Thursday morning, February 18, 1993, the New York Times published an article by reporter Lawrence Altman under the headline “Drug Mixture Halts HIV in Lab, Doctors Say in a Cautious Report.” The article said that when a Massachusetts General Hospital medical student named Yung-Kang Chow combined three anti-HIV drugs in a test tube, “the combination of drugs has blocked the virus from growing and from spreading to other cells.” It also said Chow and colleagues “noted that the test-tube strategy apparently prevented infection of healthy cells and successfully treated HIV in cells that had been infected.”
The NIH found the discovery so promising, the article said, that it planned to test Chow’s approach right away in HIV patients across the nation. Chow’s experiments had combined the commercially available drugs AZT and DDI with one of two experimental HIV drugs, the article said. But in the upcoming national trials, the AZT and DDI would be given in combination with just one experimental drug, nevirapine—a slightly less potent pharmaceutical twin of our own L–697,661.
The article quoted Dr. Martin S. Hirsch, Massachusetts General’s director of AIDS research, Chow’s supervisor, and a colleague I had long known and admired. As in any drug trials in humans, the potential existed for unfavorable interactions, Marty Hirsch told the reporter. But, he added, “No immediate adverse effects were seen at the University of Alabama in Birmingham where doctors have just started giving the combination to four patients in experiments …”
With that single hat-tip from Marty in the Times, the national media descended on Birmingham like paratroopers dropped into a war zone. CBS, CNN, NBC, and ABC producers called me in rapid sequence. “Can we come talk to you?” “We need to talk to one of the patients, can you make that happen?” “No, we need a patient of our own, we can’t use a patient who has talked to one of the other networks.”
I had ample experience with our local news folks, but the national news folks were a different breed. Like birds of prey, they swooped in aggressively and wanted exclusivity at all times. Starting Thursday and continuing through Friday, I was consumed with media interviews—in the lab, in the clinic, running from building to building. Several patients in the study had talked to media from local news outlets before, but this was very different: On a national news segment, folks they went to high school with, family members they hadn’t seen in a while, former coworkers in different cities would all see them and know their HIV status. Needless to say, most were not keen to volunteer. But a few stalwarts were, including Alan Woelhart, a study participant whose story would end up on the CBS Sunday Morning news show.
Late Friday, when I got a call from NBC, I was confused: Hadn’t I just given an NBC reporter an interview? But this was a producer from NBC’s TODAY Show. The way she peppered me with questions, I felt like I was auditioning. Apparently she was satisfied with my ability to describe the triple-drug therapy in a comprehensible way, because she invited me to be on the show the following Monday morning in New York City.
Problem: I had to be in Washington, D.C., that day for one of the major AIDS Clinical Trials Unit meetings. No problem, the producer said, “We’ll shoot you remote from our Washington bureau. We will send a car to your hotel at 5:30 a.m. Don’t wear a striped shirt. We aren’t sure yet if Katie (Couric) or Bryant (Gumbel, then the show’s two hosts) will do the interview. We’ll call you over the weekend to finalize details, okay?” The producer wound up calling three more times, including the night before the appearance, that time to mention that “Tony Fauci will be interviewed as well during your segment.”
All I could think was: I am going to be interviewed via live remote on the TODAY Show from Washington sitting next to an NIH rock star, Anthony Fauci, the consummate professional when it comes to national TV interviews. Articulate, precise, polished, with an almost unique knack for taking complex scientific concepts and presenting them in a way that Bubba in Middle America can understand. Maybe they will ask Tony all the questions and I can be his prop.
When I got to the NBC car at 5:25 a.m. in the dark streets of Washington, somehow I expected Tony Fauci to be in it. Then I remembered, he lives here; he can find his own way to the studio. I met with Tony in the “green room” waiting area after we had both had makeup applied (including, I hoped, enough powder to keep the shine down if nerves and lights made me sweat). Tony asked how the study was going, and we talked about the potential we both saw in this three-drug approach.
An associate producer came and got Tony. I had thought we would be interviewed together, but in a way, I was relieved that I’d be on my own. A few minutes later, I was escorted to a room that looked like a library, seated in front of a camera, and fitted with a microphone and earpiece. Through the earpiece, the producer advised me, “Oh, by the way, Bryant wanted to do the interview.” I had hoped for the seemingly friendlier Katie. I asked the producer if he had any tips. “Well, Bryant typically doesn’t stay with the script, so just try to stay with him.” I thought an unprintable oath—but into the mic I said, “Okay, no problem.” Gulp. I wondered if I would sprout a Nixon-esque sweat on my upper lip.
Bryant interviewed Tony first, and as usual, Tony was brilliant. Their conversation covered the basics of what triple-drug therapy was about, creating a perfect setup for me. Commercial break. “Okay, Dr. Saag, we’re back in fifteen seconds. Ready?” And then, Bryant was live: “We’re here with Dr. Michael Saag of the University of Alabama at Birmingham …”
Bryant was incisive and insightful with his questions. I kept my answers short and to the point. Before I knew it, we were done! Painless. Right when we went to break, Bryant came on my earpiece and said, “The local stations will be going to local news and weather, but we keep broadcasting to the Armed Forces Network. Can you stick around another five minutes?”
“Sure,” I said, and we continued our conversation where we left off, like we were old friends. I felt like a comic doing his first gig on The Tonight Show and getting that ultimate sign of approval from Johnny Carson, being asked over to the host’s treasured couch after I’d delivered my shtick.
If dealing with the media sometimes seemed like managing a circus, it was also strategically critical to our patients and our research. The more publically we were seen as leaders in drug development and treatment, the greater our chance to get more clinical trials, more grants, more support for our work, including our drug research. That meant more treatment options for patients and more hope.
For more than two years, we’d thought we were close to turning the tide and having something that would slow the virus. But close didn’t save a single life. My UAB colleague Jim Raper remembers it: “Everybody was sick and so many were dying. The grief was just unimaginable, every day. In that surreal situation, it felt like serendipity, or divine intervention, that I had the chance to be working at UAB with investigators like George Shaw and Beatrice Hahn and Mike Saag, where every day might bring a breakthrough. When I look back, it’s so sad to think what could have happened if Steve just had been able to hold on a few more years …”
But Jim’s partner Steve could not hold on. He had been on AZT, until that stopped working for him. And on DDI, until that stopped working, too. Jim had assumed that the great insurance coverage Steve had as a teacher would provide him with needed care—“but in Alabama, gay people were ‘just queers’ and had no kind of protection,” Jim recalls now, his gentle voice edged with bitterness. “The insurance case manager was always trying to cut some kind of a deal with me to avoid providing Steve a caregiver. I loved being with Steve even when he was sick, so when I could, I’d stay at home and provide the care he needed. We saved the insurance company lots of money.”
Steve died in July 1993. He’d been trying to reach his forty-fourth birthday. He got close.
Along with the lingering grief, Jim—a gifted, creative, generous healthcare provider—admits that there’s lingering anger. “When he died, I had to ask for time off from work; I didn’t have any bereavement leave coming because officially, Steve was nothing to me,” Jim says. “The starkness of that is still hurtful. It puts a fire in your belly for doing the right thing, so maybe other people won’t have to suffer like that in the future.” A few years ago, I shared Jim’s satisfaction when UAB instituted domestic partner benefits for same-sex couples, including family, medical, and bereavement leave.
By early 1993, Emilio Emini’s efforts to find a protease inhibitor had born fruit. A lead candidate compound that was very potent at inhibiting the HIV protease gene product was ready for testing! Based on successful efforts with L–697,661, Emilio called me and asked, “Are you ready to go another round?” I said, “Absolutely.”
Emilio flew to Birmingham to meet with George Shaw and me and plan the trial for the compound, originally called L–524 but ultimately known as indinavir. Since this drug was complicated and even perilous to produce (more on that later), only a limited amount would be available, so we made this study only for eight patients, one of whom was “Ben.”
A gay man living in Atlanta and working in real estate, Ben had the rugged good looks—dirty blond hair, penetrating blue eyes—of a Robert Redford, only taller. Friends in Atlanta’s AIDS Treatment Initiatives group told Ben that the 1917 Clinic was undertaking a study of a brand-new drug against HIV, and in July 1993, Ben was the first patient enrolled. Before he started the medicine, Ben had a CD4 count of seven and his p24 antigen was very high, over 1,000 pg/ml. Within days of starting the medicine, Ben reported how much better he already felt. By the end of the second week on the drug, all of Ben’s numbers had improved dramatically.
But early on a Saturday morning, Ben called me at home and said the whites of his eyes had turned yellow. I gulped. “How yellow?” I asked, as calmly as I could. “They’re pretty yellow.” He was describing jaundice, evidence that the drug was probably affecting his liver. In other drug studies, acute liver failure had resulted in death. Sounding more composed than I felt, I asked Ben to meet me at the clinic.
When I saw Ben, his eyes were a light canary color, but otherwise he looked as healthy as I had seen him in some time. He said he felt great and, when I examined him, I found no sign that his liver was enlarged or even tender, or any other evidence of abnormality. I drew some blood, turned on the television as a distraction while he waited, and carried the blood to the laboratory for the quickest possible processing.
Sitting with Ben while I waited for the lab’s call, thirty minutes seemed like forever. “Do I have anything to worry about?” Ben asked me. And with a straight face, I answered, “Nah, this is all a precaution. Since you are one of the first people to ever receive the drug, I just want to make extra sure that we monitor this very closely.” Inside I was thinking, I hope this medicine didn’t just kill his liver. I had six other patients lined up to take it.
In the world of drug development, liver toxicity is one of the most feared outcomes. The liver is responsible for metabolizing many of the toxins we encounter, and to the human body, drugs are just one more common toxin the liver’s designed to manage. How the liver handles the drug has a lot to do with how long the drug remains in the bloodstream, how frequently the drug is dosed, and what maximum dose can be safely given, especially over time. In a study the previous April, a few patients had been given the drug over the course of one day to see how it was absorbed and how fast the liver cleared it from the bloodstream. But no one had taken the drug for multiple days in a row before Ben, who was now two and a half weeks into his treatment.
Liver toxicity can take many forms. The most dreaded is total liver failure, where the liver cells are killed and unless a transplant happens, the patient is sure to die. In the summer of 1993, there was no way that an HIV patient would receive a liver transplant. One common sign of liver failure is elevation of the bilirubin, which causes jaundice. The other telltale sign is a spike in the bloodstream of some enzymes the liver produces. If Ben’s lab work showed that he had elevated liver enzymes as well as jaundice, that was a sure sign of liver cell injury and big trouble.
When the phone rang from the lab, I felt like running to it. But I answered it calmly, wrote down the blood test numbers—and then heaved a sigh of relief because Ben’s liver enzymes were not just normal, they were better than they had been. Though his bilirubin was up (for reasons we later recognized as being a signature but benign side effect of the drug), it was a type of bilirubin that didn’t signal liver injury. I called Emilio and explained what had transpired. After discussing it at length, Emilio and I agreed that since Ben was responding so well to the indinavir, we would pause it for three weeks and then, absent other complications, restart it. Ben agreed.
Our decision proved to be a good one. Four weeks after resuming treatment, Ben’s bilirubin had risen only a little bit, his liver enzymes remained normal—and the virus in his bloodstream, as measured by p24 antigen, had plunged from more than 1,000 pg/ml to undetectable. This response, the biggest I had ever seen to any single agent, indicated this drug was working extremely well. Ben said he felt “like a new man,” as good as he had in more than two and a half years.
About two months into Ben’s treatment, George Shaw and I sat on one end of a conference call. On the other end were Emilio Emini and Ed Scolnick, Merck’s global vice president for research and development. This was my first encounter with Ed, but I’d been told that many people who worked under him feared him and considered him a bit of a curmudgeon, gruff, opinionated, perhaps self-confident to a fault.
I told Ben’s story in full, including his latest numbers: virus undetectable by p24 antigen, and CD4 risen from seven to more than 130. “My God,” Ed exclaimed, “we’ve cured him!” Startled, George and I looked at each other incredulously. I mouthed to George, “Did he say what I think he just said?” After some awkward silence on the conference line, I got up the courage to say, “I hope he is cured, but I’m not sure I would count on that.”
While we all were excited about Ben’s success, several new challenges emerged that none of us had previously considered. Now that we knew that we had at least one drug that worked so well against HIV, how would we decide who would get it next? In the case of indinavir, this problem was compounded by the fact that it took twenty-three steps in chemical synthesis to make this particular protease inhibitor. While sufficient quantities could be made in modest-sized laboratories for the six to eight patients that we would treat in Birmingham in addition to Ben, how could Merck make enough drug to take care of the tens of thousands of people who would be clamoring for the drug over the next year, once they heard of the success that Ben had had?
For almost every drug that ultimately gets developed, the scale-up of drug production is a challenge for chemical engineers. But the twenty-three-step chemical synthesis required to produce indinavir was three to four times more steps than for most drugs—and because one of the steps was particularly volatile, it could blow up whatever plant was producing the drug if not managed properly. To Ed Scolnick and Merck’s credit, they immediately poured vast resources into building a plant for the production of this drug at incredible speed. But even with the most optimistic estimates, they were at least nine to twelve months away from having large quantities of drug that met good manufacturing practices.
Recognizing this challenge, George and I agreed that at least for the time being, we would keep the success of Ben’s treatment to ourselves. Once we could be confident that Merck would be able to produce the drug in sufficient quantities to be able to meet more of the need, we could break our silence.
George and I had gotten permission from Emilio to send small samples of Ben’s blood to Jeff Lifson and Mike Piatak in Redwood City so that they could perform the QC-PCR test. Ben’s PCR value prior to treatment was well over one million copies of virus per milliliter—but four weeks into treatment, just after the time Ben showed up with jaundice, his QC-PCR value had dropped below 1,000 copies, about the limit of the assay’s detection capacity at that point. This degree of suppression of virus had never before been achieved and was truly breathtaking.
The good news didn’t last. In early November, Jeff’s test results showed the virus in Ben’s blood was starting to rise again. George and I called Emilio, and he confirmed our conclusion: Albeit slowly, Ben’s virus was becoming resistant to the drug that was saving his life. Emilio’s response was precisely what I knew it would be: “I hate this virus!”
Notwithstanding Ben’s developing resistance, he and the other participants in our indinavir monotherapy trial were still benefitting tremendously from taking the drug. But because it was in short supply and we lacked knowledge regarding its potential lasting benefit, we elected not to broadcast our findings. It was a brutally hard decision. Dozens of patients in our clinic and scores of patients I knew from Atlanta were in dire need of something, anything, that could bridge them to the next new drug, the next new finding. On each call with Emilio I would ask, “When is our next study?” “How soon could I get my other patients on this drug?” Looking at days on the calendar, I didn’t have to wait long, but seeing patients in the clinic, the wait for the next study was agonizingly slow.
Marty Delaney, Tom Blount, and their fellow activists knew that there were limited slots in clinical studies and that only a few US cities had sites that hosted trials. They pushed pharmaceutical companies to expand their compassionate use programs as widely and quickly as drug production would allow and the FDA to accelerate approval of new drugs. To create more even access, Marty spearheaded a creative solution, the Parallel Track. While companies continued development of promising new agents through their traditional Phase II and III clinical studies, they would also create a centralized access program that would allow any clinician in practice to sign up for the program and have the drug delivered to his or her clinic for distribution to patients in the most need of access to the drug immediately. But these were institutional solutions, and institutions seldom move quickly.
Tom needed a solution now—or sooner, or yesterday—because his beloved, Jim Straley, was wasting away before his eyes. Jim was like so many other patients at this time: Their disease would almost surely have killed them by the late 1980s, but they were saved by AZT. Then the benefits of AZT became exhausted and they moved on to the next wave of newly released drugs—DDI, DDC, D4T—but the incremental benefit of these drugs when used after AZT failure was small. Hoffman-La Roche was the first to market with an approved protease inhibitor, saquinavir, but it was so poorly absorbed from the gut that very little drug made it into the circulation. Better, more potent drugs were needed. And for Jim and many others, there was no time to waste.
Tom and other activists made it their business to know which companies had what drugs in which stages of development, and which providers and trials had the most promising ones. They were relentless in seeking ways to get more drugs sooner for the use of the most desperately ill. This was Tom’s quest on a humanitarian level to help anyone with HIV, and on an excruciatingly personal level to help Jim. In June 1994, when Jim’s numbers disqualified him for inclusion in a study of L–524/indinavir, Tom pleaded for an exception to get Jim the drug. I could not support his plea in a conversation with Merck officials. In response, Tom faxed me a four-page letter full of agony, anger, and reproach.
“Only once has Jim been able to qualify for a clinical trial, and now, apparently, he never will have that chance again,” Tom wrote. “Even as inclusion criteria were relaxed, he was always a few T-cells too short … His only hope has been that someone in the medical field would become interested in salvaging his life, his only available avenue is compassionate use, and the most feasible tool is L–524 … All we were asking for was twelve days’ use of this drug, and no matter how rare it is, I can’t believe that Jim’s life has such little value to everyone but me. As long as there is a single dose of L524 that is not critically needed for research (and we both know they are there), I believe that the decision to not allow at least some compassionate use is completely immoral … The really sad thing, personally, about this development is that I truly believe Jim’s life could have been saved by L–524.”
Tom admits that he never expected to hear from me again after the “neck-wringing” (his words) that he gave me in that letter. And he did sound surprised when I telephoned him to thank him for his insight and candor. I think we each knew the other was trying to act ethically and with good intentions. I never begrudged Tom his view, and I was in awe of his determination. He literally worked every angle to try to get L–524 for Jim and others. He worked his connections on the Merck citizens’ advisory board. He supported an underground effort to manufacture the drug privately. Tom’s father even joined the effort, pleading Tom’s case in a personal note to a friend of his who happened to be Merck’s chairman.
“In late 1994 when I was chasing that drug, I think there were thirty-two or thirty-three humans taking it in clinical trials around the country, and through my work I knew thirty of them,” Tom recalls. “I got people to give me a pill or two, to sneak it out of the trial, so that by the end of the year I had a thirty-day supply of L–524.”
Then, early in January 1995, Tom phoned me to say Jim was on his deathbed. Tom did not say how he got a thirty-day supply of L–524 and I did not ask—but he wanted a doctor’s opinion on whether he should go ahead and start Jim on the drug, knowing that he might not be able to get any more. I told him, “Tom, do it.” Even though starting a drug Jim could not continue might have built resistance to further treatment, in Tom’s position, I would have done the same thing. On January 11, Tom gave Jim his first dose of L–524, then caught a 7:00 a.m. flight to New Jersey to talk to Merck officials about increasing access to the drug.
In a meeting that included Paul Reider, head of production at Merck, Tom pleaded for a compassionate use program that would provide L–524 immediately to patients who might not live until its FDA approval. Here’s how Tom remembers it:
Paul argued that Merck’s plants could barely produce enough drug to supply the patients in clinical trials, and could not spare any for other patients. We had intelligence that said Merck did have L524 to spare, perhaps enough for 450 people. I was thinking of Jim and others at death’s door, and I was weeping with rage. I had to leave the meeting to catch a 3:30 p.m. flight, to get home to give Jim his second dose of L524. But as I walked out the door, I turned and pointed at Paul and shouted, “We are talking about maybe 450 people, a fully-loaded 747 jet—and it’s going down and you have the possibility to prevent that! Those lives are on you.”
Tom made it back to Atlanta to give Jim his 6:00 p.m. medication. The next day, as Tom recalls it, “Jim sprang out of bed for the first time in months. And Paul Reider called to tell me that he and other Merck officials had been deeply affected by what I said, and they were determined to get the drug out to more people. In a couple of months, they did.” Tom didn’t know until later why his 747 metaphor had hit so hard at Merck. It was because Dr. Irving Sigal—the Merck chemist who was most responsible for the discovery of L–524—had been on Pan Am Flight 103 on December 21, 1988, when a bomb destroyed the plane over Lockerbie, Scotland, killing all on board.
After first seeing dramatic benefit from L–524, Jim developed resistance to it. Tom sought other remedies, but Jim was so depleted that nothing helped for long. Jim Straley was forty-two when he died on August 20, 1995. Ask Tom how long they were together, and he will tell you. They had “eighteen years, thirty days, and twelve hours.”
When George and I were writing the paper on L–697,661 on Beatrice’s grandmother’s “good luck table,” we made a glancing reference to how rapidly the AIDS virus must replicate. But it was not until we started looking carefully at the drop in HIV RNA, or viral load, in Ben’s case that we finally asked the pointed question: “Just how rapid is rapid?”
To help us fashion an answer, we recruited Martin Nowak. A young Vienna-born mathematician who—George met at a professional meeting, Martin could create mathematical formulas to describe almost anything, from the seasonal patterns of bird migrations to the performance of professional bicyclists. We agreed he was the perfect person to work with us on modeling the virus’s behavior during Ben’s use of indinavir.
After several months of work together, George, Martin, Emilio, and I were able to describe an almost mind-boggling process of dynamic replication. George and I hadn’t known the half of it—this viral replication wasn’t just rapid, it was incredibly rapid. And relentless—the virus never stopped replicating. Other viral infections, such as influenza, produce up to 1 million copies per day. With HIV, between 1 billion and 10 billion viruses were produced in any given day, every day from the time a person was first infected until the time he or she succumbed. The virus would infect a cell somewhere in the body, typically in lymphoid tissue such as the spleen, a lymph node, or the gut, and convert that cell into a virus factory. In the day or less that each infected cell lived, the cell would produce several thousand viral particles, and then the virus would kill it just as another susceptible cell became infected to take its place.
Once, the central mystery of HIV had been why patients progressed from an asymptomatic state to illness and then death, a process that takes on average 12–15 years. But when we saw these numbers, I was more amazed that patients lived as long as they did under such an onslaught. Another eureka moment! It is a real tribute to the resiliency of the human body that such a challenge can be managed by the patient for so long without showing signs of infection or disease. When we give antiretroviral therapy, we block the ability of the virus to infect neighboring cells. Then when the cells producing virus die off, usually within a day, they are not replaced with a newly infected cell, and the amount of virus produced in the body is reduced exponentially. So as rapidly as the virus had been produced, it also could be seen to decline very rapidly in the bloodstream, by the QC-PCR assay.
Medical science works best when discoveries like these are shared freely and promptly, for others to refine and build upon. Such findings often are disseminated via national and international scientific conferences where investigators submit condensed abstracts of their work that are reviewed by peers in the field and judged to be of sufficient quality to warrant presentation. The scientific abstracts considered of greatest interest typically are showcased as oral presentations at the meeting, usually in front of large audiences. When not presented orally, the other accepted abstracts are presented at poster sessions, where the investigators summarize their data and conclusions on five-by-seven-foot posters, scores of which are displayed like billboards in the conference hall. Investigators stand by their posters at designated times during the conference, presenting repeatedly to whoever stops by and wants to hear the story of their work.
In October 1994, I was invited to present an oral abstract at the meeting of a leading ID organization, the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). George, Martin, Emilio, and I had submitted an abstract on the viral responses to regimens using nevirapine combined with two or three other drugs, the so-called “triple-drug cocktails” that had gotten us so much media attention the previous year. While the results of our study did indeed show a benefit of triple-drug therapy over dual therapy, we had a different story to tell.
In addition to modeling the viral dynamics of the indinavir patients, we also had modeled some of the patients on triple-drug therapy and had seen the same story of 1 billion to 10 billion viruses produced per day, life span of an infected cell of approximately one day, and rapid decline of viral load in just weeks, or even days, of therapy. This was the story we wanted to tell.
Our triple-drug therapy trial was slated as an oral abstract, in the same session where Dr. David Ho was scheduled to tell the story of ritonavir, a protease inhibitor similar to indinavir but with substantially more side effects, especially nausea, stomach upset, and diarrhea. David and his team at Los Angeles’s Cedars-Sinai Medical Center had been performing similar modeling exercises, except instead of working with Martin Nowak, he was working with a mathematical modeler at Los Alamos, Alan Perelson. Astonishingly, they had precisely the same findings we did regarding the dynamics and they too wanted to highlight their findings in the upcoming session at ICAAC.
For me, this was a deja vu moment. Four years earlier, at the 1990 International AIDS Conference in San Francisco, George and I had submitted an abstract describing the quantitation of virus from several patients (including WEAU) who presented early with acute HIV infection, using serial culture techniques and comparing the results from this technique to other quantitative measures such as p24 antigen. This study was the precursor to the study we eventually did with Jeff Lifson and Mike Piatak using QC-PCR, where we ultimately saw extremely high levels of virus, on the order of 1–10 million copies per milliliter among those with acute infection. I had my poster printed and ready to be hung in the conference hall the following morning.
Sunday evening around 8:00 I was in my hotel room and had just picked up my meeting materials, including my badge to get into the sessions and the abstract book. I hadn’t gotten very far through the abstract book when I stumbled across an abstract from the Cedars-Sinai group describing virtually the same findings we were presenting in our abstract! Almost identical. I called George.
The lead author on the abstract was Eric Daar, a fellow then working in the lab of David Ho. (Eric has since gone on to become a leader in the HIV field in his own right and is now the division director of ID at Cedars). David Ho grew up in Los Angeles and had done his training in ID at Massachusetts General Hospital working in the lab of Marty Hirsch. He returned to Los Angeles where he started his own lab and was working on HIV pathogenesis. He had completed a prior study of quantitating HIV by culture techniques in the spinal fluid and later a study of HIV in the bloodstream using culture techniques. I remember that study in particular because it mirrored precisely what George, Beatrice, and I had been doing in the lab—but David published his findings first, scooping our findings in the literature. We ultimately got our study published, but we clearly were “seconding” David’s study.
As I stared at the abstract in the book that Sunday night, I thought, “Damn, we got scooped again by David Ho!” George calmed me down, telling me to go to the conference hall in the morning, track down Eric Daar to see where they were in terms of publication deadlines, and get back to him.
As soon as the doors opened at the convention hall, I raced to Eric’s poster showing data that mirrored ours almost point by point. As I was looking it over, Eric came by. I introduced myself and shared our data with him. He was intrigued. I asked where they were in the publication cycle and he said they were getting ready to write it up. I suggested, “Maybe we could submit back-to-back in the same journal?” “Fine with me,” he said, “but it’s really up to David.” I asked George to call David. We worked on the papers simultaneously and published them back-to-back in the New England Journal of Medicine.
For scientists, the issue of competition is tricky. Like athletes in a team sport, our first allegiance needs to be to the team, and in a sense, David Ho and I and our colleagues were all on one team fighting HIV/AIDS. But in another sense, science isn’t a team career: Scientists are individuals when it comes to being offered professorships, endowed chairs, equipped and staffed laboratories, salaries, and benefit packages. In this instance, the team had won. It felt good.
Standing outside the large auditorium at the ICAAC meeting in Orlando, I visited with David Ho. I mentioned how similar this was to our prior experience and wondered out loud if we might try publishing our findings once again back-to-back. He thought that was a good idea, but he was more focused on how we would coordinate our talks coming up in the next hour. We agreed that he would present his approach to modeling viral dynamics, with a focus on the methodology. Since my talk was initially based on the clinical findings from the triple-drug therapy trial, I focused my talk on the clinical meaning of the viral dynamics findings—that there was no virologic latency but instead a constant assault, eroding the immune system’s reserves until there was nothing left to fight off opportunistic diseases. This viral churning also burned a lot of energy and caused a great deal of inflammation that, over time, reduced appetite and led to wasting.
To me, these data were urgent proof that the virus needed to be treated early and aggressively. David concurred. Over the weeks following the ICAAC meeting, David’s group and our group pulled our manuscripts together and submitted them to Nature, where they were published back-to-back.
Earlier in 1994, a message I had received from David Ho had made me feel that we really were on the same team, in a much more personal way. He knew I was on the West Coast for an IAS-USA continuing medical education meeting and wondered if, while there, I could go by and see a patient who was struggling, on whose case he had consulted. I said, “Sure,” and gave my hotel address to the car service that was to ferry me to the patient.
At the appointed hour, I went to meet the car and found a gleaming, full-sized limo. I don’t remember the chitchat with the driver; I was taking in the view as we drove along palm-tree-lined boulevards, past successively ritzier mansions. At our destination, the driver pulled the limo up to the doors of an elegant Spanish-hacienda-style home, ushered me out of the car, and told me to ring the intercom. When I did, a woman’s voice greeted me: “Dr. Saag, come on in, the door’s open. Come up the stairs and turn right, I’m at the end of the hall.”
It felt kind of eerie to walk into the exquisite, high-ceilinged house and see no one. Then I saw the scattering of toys in the living room and my tension eased: I was just a doctor, making a house call to a sick mom. I headed up the grand staircase.
Elizabeth Glaser was standing at the end of the hall in a pink velour robe, a frailer version of the outspoken advocate I had seen behind podiums and on television. After quick hellos, she described her concern: “I have this horrible pain, in my back and down my legs, and I can hardly walk.” My fear immediately was cytomegalovirus, an infection that can be dormant and harmless in healthy individuals but that can cause shooting pain, muscle weakness, and other problems in people with compromised immune systems. I examined Mrs. Glaser and told her what I thought the problem might be. I told her I would like to start her on two medications that would help until I could talk to her doctor (Dr. Michael Gottlieb) about confirming my tentative diagnosis with a spinal tap. She thanked me and asked if I could find my way out. I returned to the front door, where the driver was waiting.
In 1981 when Elizabeth Glaser was giving birth to her first child with her husband, actor Paul Michael Glaser, she hemorrhaged and required a blood transfusion. Four years later, she learned that she had contracted HIV from the transfusion and that she had passed it to her daughter, Ariel, through breast milk and her second child, Jake, in utero. In 1988, Ariel died. On July 14, 1992, in New York City, Elizabeth gave a speech to the Democratic National Convention in which she vented her outrage at “leaders who say they care but do nothing.” In her speech, I heard the cry of anyone who ever has faced devastating illness and felt ignored or ill-treated:
I am in a race with the clock. This is not about being a Republican or an Independent or a Democrat. It’s about the future for each and every one of us. I started out just a mom, fighting for the life of her child. But along the way, I learned how unfair America can be today. Not just for people who have HIV but for many, many people. Poor people. Gay people. People of color. Children. A strange spokesperson for such a group, a well-to-do white woman. But I learned my lesson the hard way and I know that America has lost her path and is at risk of losing her soul. America, wake up! We are all in a struggle between life and death.
I understand the sense of frustration and despair in our country because I know firsthand about shouting for help and getting no answer … When you cry for help and no one listens, you start to lose your hope. I began to lose faith in America. I felt my country was letting me down, and it was. This is not the America I was raised to be proud of. I was raised to believe that others’ problems were my problems as well. But when I tell most people about HIV in hopes that they will help and care, I see the look in their eyes. “It’s not my problem,” they’re thinking. Well, it’s everyone’s problem …
I believe in America, but not with a leadership of selfishness and greed where the wealthy get health care and insurance and the poor don’t … We need health care for all.
I knew when I saw Mrs. Glaser that there was little that I, or any physician, could do. She died a few months later, but her valiance lives on in the work of the Elizabeth Glaser Pediatric AIDS Foundation—and in her son, Jake, now in his late twenties.
The Nature articles on which my UAB colleagues and David Ho’s crew collaborated were published back-to-back in the January 1995 issue—another team win! And in August 1995, David hammered home the point in an editorial in the New England Journal of Medicine, headlined “Time to Hit HIV, Early and Hard.”
Publication of the viral dynamics paper was perhaps the most meaningful scientific experience I have ever been a part of, not because I was a researcher but because I am a physician. I wasn’t senior author or first author, indicating I wasn’t the first prime mover of the project. But I was part of the team, contributing the clinical meaning of the findings to the discussions and the paper. These findings, to me, indicated we had an angle on the virus for the first time. We could beat it—or at least we could manage it. I had something that could give my patients what most they craved: time.
The viral dynamics story took our understanding to a new level. We now had a clear view of how the virus caused sickness and what we could do to retard and hopefully reverse its progression. Stop the replication, stop the disease. It was that simple and that profound.
The inhibition of replication had to be complete and persistent, 24/7, day in and day out, fifty-two weeks a year, every year for the rest of the patient’s life. It would take a combination of drugs, the so-called cocktail—and once successful drug cocktails were discovered, they had to be taken every day, all the time. Failure to do this would lead to drug resistance and return of the disease process, picking up from the time the drugs stopped. That ultimately would take the patient back to the point where he or she was prior to initiation of the cocktail and back on the doomed path to sickness, AIDS, and death.
And the viral dynamics discovery had an added bonus: For the first time we could see a clear path to a cure of HIV. More than 99 percent of cells producing virus naturally die off almost immediately, and with treatment they are not replaced by newly infected cells.
A very small fraction of infected cells, however, don’t die. They persist as chronically infected cells, not actively producing virus but still harboring the virus in the host’s DNA, ready for reactivation at some distant point in the future. The scientists’ favorite guess is that the reason they persist is precisely because they are not actively producing virus and therefore aren’t killed by any of the proposed mechanisms outlined above.
Were it not for this reservoir of longer-lived, chronically infected cells, the antiretroviral cocktail would lead to cure in everyone because the other infected cells die and are not replaced. An apparent example of this was the headline-making report at the 2013 Conference on Retroviruses and Opportunities Infections (CROI) describing a Mississippi case in which an infant was HIV-positive at birth, was started on aggressive antiretroviral therapy within hours of birth, and was later found to be free of the virus—essentially, cured. In this case, the infant’s virus did not have sufficient time to establish the latent reservoir before treatment began. So when the replication was stopped, the infected cells died and were not replaced. Since no latent cells were present that could carry the infection forward, the child was cured. Further proof of principle!
Because most patients, unlike that infant, will not start treatment before the reservoir is established, the question becomes: How long do the chronically infected cells live? The answer to this question tells us how long we have to wait until patients are cured.
Initial estimates provided by Martin Nowak in our group and Alan Perelson in David Ho’s group suggested that the half-life of the cells was between fourteen and thirty days. This meant that during that time frame, roughly half of the cells would die. So if we waited enough half-lives, the last remaining cells would die off, resulting in cure. In this model, it is much like uranium: How many radioactive half-lives would we wait until, say, we would let our kids play near Japan’s Fukushima I nuclear power plant after the 2011 partial meltdown there? With the cell half-lives that our modelers had devised, it would take three or four years for the latent reservoir to disappear, at which point the patient would be cured. This was real news—and while it took a while for the news to sink in, there was ultimate recognition of the finding in the public media when David Ho was named TIME magazine’s “Man of the Year” in 1996.
Then, a not-so-funny thing happened on the way to the cure. With more study and reevaluation, it became clear that the cells actually lived on average for thirty to forty months, not days. When that number is plugged into the “uranium equation,” it turned out that it would take more than seventy years (!) of full suppression of the virus for all the cells to die off and result in a cure.
Elimination of the latent cell reservoir through more extreme measures, such as ablative bone marrow transplant, has since been shown to lead to cure in a few patients in the last several years. That confirms the theoretical model as proposed by the Ho group and our group in 1995, and it was something I would explore a few years later for a patient of mine, Cyndie Culpeper. But it was (and for the foreseeable future, would be) an extreme solution that might help a few.
Translating findings from a model to a person—in this case, our patients—matters. Discussions of models, replication inhibition, mathematical abstractions, academic papers, and authorship all speak to the world of science; these things matter too. But when the conferences end and we get off the airplane near home, those of us who were lauded by colleagues for our papers came back feeling less than triumphant. Dealing with the relentlessness of HIV always took us back to people who had entrusted their lives to our care. In our brief absence, new symptoms had surfaced for one patient and another had taken a nosedive. In a very real sense, this work wasn’t about David Ho or Mike Saag or some unknown research assistant. It was about Steve or Brian—or Ben.
In mid-March 1996, in what was then the fastest drug approval in FDA history, the agency approved the drug first known as compound L–524, then as indinavir, and commercially as Crixivan. By then, Ben had been on the drug for more than two and a half years, and we had intensified his regimen with AZT and 3TC, a new drug similar to AZT but with fewer side effects. Ben clearly was ahead of his time, because that combination—indinavir, AZT, and 3TC—would become the “triple-drug cocktail” that marked the beginning of the Highly Active Antiretroviral Therapy (HAART) era.
Ben’s virus never stopped battering away at the main drug in his regimen. When the virus finally figured out indinavir, we tried other antiretroviral combinations, but to no avail. Ben died from advanced AIDS in spring 1998. By bravely volunteering for the L–524 trial in summer 1993, Ben had bought himself nearly five years of life. How many years his generosity, humor, and courage added to the lives of others with HIV we will never know, but if we added them all we’d be talking about centuries. He lived for others, and died among the epidemic’s unsung heroes.