25 years of HAART

These days, it is quite possible to take for granted the fact that we have lifesaving medications for HIV. In fact, it is so easy to take for granted that I forgot to write this article for a whole year! That’s right—as we entered 2021, I got it in my head to write an article about 25 years of effective treatment for HIV (what used to be called “highly active antiretroviral therapy,” or HAART, but is now simply called ART—a reflection of how we now take the “highly active” part completely for granted). But I was so caught up with COVID (vaccines, good; delta variant, bad), and the presidential election, and the January 6 insurrection at the Capitol, and the trial of Derek Chauvin in the spring, and the wildfires in the West over the summer, and the spate of extreme weather events nationwide in the fall, and the wave of voter suppression laws, and the battle in Congress over infrastructure, and on and on and on, that I forgot to pitch the article to my editor until it was too late to run it in 2021. 

Okay, so that lapse was largely due to my own scattered brain; but I really do think it is worth noting that we have so much momentous, historic, unprecedented “stuff” (by which I really mean an expletive known for hitting the fan) going on in this country and in the world right now, that the Herculean/Amazonian strides we as the human race have made against HIV since the AIDS epidemic began in 1981 can easily fade from our collective view. And maybe that’s a good thing. Maybe that means HIV and AIDS are, though by no means in the rearview mirror, nevertheless something we more or less know what to do about—provided we can muster the political will and the human and financial resources to do it, whether in sub-Saharan Africa, or in hard-hit urban and rural parts of the United States, or elsewhere around the world. 

Nevertheless, as a person who has been living with HIV for some 30 years now, while I may be a day (or a year) late, I am loathe to be even a single dollar short, and am grateful that Positively Aware has agreed to publish my love letter to 25 years of HAART in this issue. And in fact, since HAART as we know it was more or less born at the XI International AIDS Conference, held in Vancouver, Canada, in early July of 1996, I guess I still have six months or so before HAART actually turns 26. 

Anyone reading this article who wasn’t living with HIV in 1996, or who was not otherwise involved in what we then referred to as the AIDS community—or, as I’m sure is the case for many readers, not even born yet—you may well be asking, What is this HAART of which you speak, what is so important about it, what does it mean for me now, and what are its implications for my future? Good questions! Let’s address them one by one. 

Let’s start with what I like to think of as the catechism of the early AIDS epidemic. The first signs of the emerging epidemic appeared in the spring and summer of 1981, with the mysterious appearance of unusual infections and cancers predominantly among young gay men in New York, San Francisco, and Los Angeles, including Pneumocystis carinii (later renamed Pneumocystis jiroveci) pneumonia (PCP) and Kaposi sarcoma (KS). While it was not immediately clear what was behind these outbreaks, the unusual infections and cancers were all associated with compromised cellular immunity. Since the first outbreaks reported were among gay men, medical experts initially called the condition Gay-Related Immune Disorder (GRID). Soon, however, it became clear that the phenomenon was occurring among other groups as well, including injection drug users, the sexual partners of injection drug users, the newborn children of women who injected drugs or whose male partners may have done so, certain national groups (such as Haitians), and certain recipients of blood products (such as hemophiliacs). Consequently, the disorder was renamed Acquired Immune Deficiency Syndrome (AIDS). It became increasingly clear that AIDS was associated with an infectious agent that resided in certain cells (transmitted through blood, semen, vaginal fluid, and breast milk), which explained its transmission via sexual intercourse (anal and vaginal), through sharing needles to inject drugs, through receipt of contaminated blood products in medical procedures, and from mothers to infants either during delivery or when breastfeeding. At this point, the infectious agent remained unidentified, and without an infectious agent to target, the prospects for treatment were slim to none. 

A virus that appeared to be associated with AIDS was isolated in 1983 by Luc Montagnier’s team at the Pasteur Institute in Paris. In 1984, two other teams confirmed the association of this newly identified virus with AIDS—Robert Gallo’s team at the National Cancer Institute in Bethesda, Maryland, and a team of scientists from the University of California, San Francisco, and the California Department of Health Services in Berkeley. Initially called lymphadenopathy-associated virus (LAV) by Montagnier and human T cell leukemia virus type III (HTLV III) by Gallo, a group of scientists eventually agreed on the name human immunodeficiency virus (HIV), the name we know it by today. 

Now that a virus had been identified, the search for a treatment could begin in earnest. But that was much easier said than done. In 1983, the field of antiviral development was still in its infancy. The first antivirals to be approved by the U.S. Food and Drug Administration (FDA) and marketed for clinical use targeted the herpes simplex virus (HSV). Dendrid (idoxuridine), an ophthalmic solution (eye drops), was approved by the FDA in 1963 to treat eye infections caused by HSV. Then, in 1982, a decade into the genital herpes epidemic that came in the wake of the sexual revolution of the 1960s, the FDA approved Zovirax (acyclovir) ointment to treat genital herpes—and with that, the antiviral era entered high gear. 

Herpes viruses belong to a large group of viruses called DNA viruses. A DNA virus is a virus that has a genome (the complete set of genetic material in a cell or microbial organism) made of deoxyribonucleic acid (DNA) that is replicated (reproduced) by an enzyme called DNA polymerase. The DNA polymerase makes new DNA by building up a chain of nucleotides, the basic building blocks of nucleic acids. Stick a wrench in the works of the DNA polymerase, and you stop the virus from replicating. That’s what drugs such as idoxuridine and acyclovir do, in a process called DNA chain termination.

By contrast, HIV is a retrovirus. As the prefix “retro” suggests, retroviruses do things the reverse of how we usually think of cellular metabolism. In most viruses, as in most cells, DNA copies its genetic code into ribonucleic acid (RNA) in a process called “transcription,” and RNA synthesizes all the proteins that carry out the life processes of the cell or virus. In the case of retroviruses, RNA, not DNA, is the basic genetic material. In a process called “reverse transcription,” retroviral RNA encodes its genome into DNA, which the virus then inserts into the genome of the infected cell. The retrovirus, in essence, “hijacks” the host cell, turning it into a cellular factory for its own replication. 

The first drug to treat HIV infection

At the time HIV was identified as the virus that causes AIDS, medical science had developed a number of antiviral agents targeting DNA viruses, but no antiviral agents that targeted retroviruses. Now, the search was on for antiretroviral drugs to treat HIV. Medical scientists began screening a wide range of existing drugs to identify ones that might show efficacy against HIV. Researchers at the drug company Burroughs Wellcome (which later became Glaxo Wellcome, and later still GlaxoSmithKline, and most recently spun off a subsidiary called ViiV, focused on HIV drugs) struck it lucky with a drug called azithrothymidine (AZT), first developed in 1964 to treat cancer, but shelved when it failed to show any anticancer effect. The drug was later given the generic name zidovudine, and approved in 1987 under the brand name Retrovir, but will forever be known in popular parlance as AZT. It belongs to a class of drugs called reverse transcriptase inhibitors (NRTIs), which interrupt the stage in the viral life cycle where viral RNA transcribes its genetic code into DNA. 

While AZT decreased opportunistic infections and deaths among people with AIDS, it had serious side effects, especially anemia (low red blood cells) and neutropenia (low white blood cells) at the initially prescribed dose of 1,500 mg daily. The word on the street in the AIDS community back then was that AZT was poison, a treatment worse than the disease. That anger and frustration is completely understandable given the circumstances. But the fact is, AZT is a good drug that was being used in a bad way. That was not anyone’s fault, per se. At the time, ART was a whole new ball game, and researchers and clinicians alike were playing without much of a rule book. A clinical trial in 1990 not only reaffirmed the efficacy of AZT, but showed that it could safely and effectively be used at a much lower dose than before, and in fact, performed better overall because people taking the drug were no longer beset with such severe side effects.

The big problem that remained with AZT, however, was viral resistance. Viruses mutate, and retroviruses mutate at a much higher rate than other types of viruses. Mutations are changes in the genetic makeup of the virus that emerge in response to what is called “selective pressure.” It’s all about Darwinian principles of evolution—survival of the fittest. Over hundreds or thousands of years, people or animals may change their appearance or develop new behavioral traits (lighter or darker skin, greater running speed, sharper teeth, etc.) in response to new conditions or elements in their environment, like climate or predators. We say these environmental pressures “select for” particular genetic mutations. The same thing happens to viruses under what is called selective drug pressure. The virus is always mutating. Absent the presence of a drug like AZT, the HIV population is dominated by the “wild type” virus, with its sort of starter kit of genes—the Legos that come in the original box. But when a new drug comes to town, like AZT, the wild type virus gets displaced, while certain mutations confer a survival benefit—turn HIV into viral cockroaches that refuse to die. Over time, the mutant virus becomes the dominant strain over the wild virus. In the early days of AZT, this process begins to happen within a matter of weeks after starting treatment, and led to multiple mutations that conferred high-level resistance. People got better for a while, but then they got sick again, and eventually died of AIDS-related complications. AZT—at least when used by itself—improved health and extended survival, but only temporarily. In medical terms, we would say the response to AZT was remarkably robust, but not sustained. It worked, but only for a while. 

More NRTIs and the advent of dual combination therapy

The pharmacologists and research clinicians working to develop treatments for HIV were no dopes; in fact, they were some of the smartest, most resourceful, most dogged and determined medical scientists the world has ever known. They got the drill on viral resistance early in the fight, and moved right on to plan B, which was combination therapy—using combinations of antiretroviral drugs to stymie the emergence of viral resistance, setting up multiple genetic barriers, as it were, so that HIV could no longer mutate its way out from under the drugs. Of course, combination therapy required drugs to combine. That came to pass, but at an excruciatingly slow pace. After AZT in 1987, it took several years to roll out four more NRTIs: Videx (didanosine, ddI) in 1991; Hivid (zalcitabine, ddC) in 1992; Zerit (stavudine, d4T) in 1994; and Epivir (lamivudine, 3TC) in 1995. 

After the introduction of the newer NRTIs, a series of large clinical trials showed that dual combination therapy with AZT and another NRTI was better than AZT alone at delaying disease progression and reducing mortality. These trials also suggested that combination therapy is beneficial for asymptomatic patients with CD4 counts less than 500 cells/µL. These studies—with arcane names like ACTG 175, Delta, CPCRA, and CAESAR—all released their preliminary findings in 1995, and their findings collectively brought an end to the era of antiretroviral monotherapy. In the wake of these findings, the International AIDS Society–USA in 1996 issued the first published guidelines for ART. The regimens recommended for initial therapy in these guidelines included AZT+ddI, AZT+ddC, and AZT+3TC. 

On the downside—and it was a big downside—these trials also showed that there was no clear benefit to dual combo NRTI therapy for people with AIDS who had already been on AZT monotherapy. The same would prove to be true for people who had previously been on any NRTI monotherapy. This was a heartbreaking situation for the AIDS community at the time, as many people with AIDS “burned through” one NRTI monotherapy after another. As each new drug came to market, medical providers tried desperately to provide those in their care with even an additional year or two, in some cases even a few additional months of life. In each case, however, the benefits of NRTI monotherapy quickly waned in the face of viral resistance, and the new dual combination regimens did little or nothing to restore health or prolong life for these highly treatment-experienced individuals.

New drug classes and the coming of ‘the cocktail’

Meanwhile, something big—something very, very big—was brewing in the research laboratories of the major drug companies, the academic medical centers, and clinical trial sites across the country and around the world. Two new classes of antiretroviral drugs were being evaluated in clinical trials—nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). The investigational (that’s shop lingo for experimental) NNRTIs targeted the reverse transcription stage of the HIV life cycle, just like the NRTIs, but via a different molecular mechanism. The PIs, as their name suggests, inhibit a viral enzyme called protease, a sort of viral scissors that cut long protein chains into shorter fragments during viral replication. 

The crucial turn of events, however, was not merely the availability of two new drug classes, but also the fact that these new drugs could be used in triple drug combinations. Medical science already knew that two drugs were better than one, but still not quite good enough. Now, adding a third drug—that might prove to be a real game changer!

And in fact, it did. For several years, the international AIDS conferences had reported only incremental progress in the scientific and medical effort to treat HIV. New NRTI monotherapies raised the hopes of people with HIV and AIDS excited at the conference in Berlin in 1993, but were ultimately disappointing. Dual combination therapy showed promising results in Yokohama in 1994, but no brass ring. In fact, progress had become so incremental that the organizers decided to hold the international AIDS conference only every other year. I remember going to a meeting for community members in some big auditorium somewhere in New York, maybe the Great Hall at Cooper Union or someplace like that, where trusted messengers like Dr. Marty Markowitz presented data on the new PIs, all four of them—saquinavir, indinavir, ritonavir, and nelfinavir (none of them even had brand names yet). It was a very emotional time. We wanted to hope, but we were also afraid to hope. We had been disappointed so many times. We had buried so many friends and loved ones, attended so many memorials. And here were these experts telling us to hold on just a little longer. It wasn’t just that a new drug meant a few more months of health or life; it was the idea that maybe finally, by erecting a high enough barrier to resistance, by closing off enough escape routes, we could achieve not only robust but also sustained suppression of HIV. 

The XI International AIDS Conference in Vancouver in July 1996 was a moment of great hope and great expectation that for once, finally, did not run up against a cold, hard wall of disappointment, but rather made good on its promise. The findings reported on various combinations of a dual NRTI “backbone” plus either a PI or an NNRTI were not merely encouraging, they were exhilarating. The researchers called this new kind of treatment highly active antiretroviral therapy, or HAART, to distinguish it from all the previous incarnations of ART that had been stopgap measures at best, and cruel jokes at worst. 

“From AIDS Conference, Talk of Life, Not Death,” announced a headline in The New York Times on July 15, 1996. The media were abuzz with news of the revolutionary new “drug cocktail” that had been unveiled in Vancouver. While there were several triple-combination regimens that boasted good results, a clear winner did emerge from the conference—an NRTI backbone of AZT/3TC combined with the PI marketed as Crixivan (indinavir, IDV). 

In the following years, there would continue to be ups and down, successes and failures, challenges as well as opportunities. For example, the initial NNRTIs had a very low genetic barrier to resistance. In fact, a single mutation could knock out not only the drug you were taking, but the entire NNRTI class (a phenomenon called cross resistance or, at this extreme, class resistance). The PIs, particularly Crixivan, appeared to be associated with disfiguring and debilitating types of fat redistribution, collectively known as lipodystrophy or lipoatrophy, and described by terms like “buffalo hump” and “Crix belly.” Crixivan was also associated with kidney stones (which, in case you didn’t know, are really awful things to have). Norvir (ritonavir, RTV) was associated with severe gastrointestinal (GI) side effects (nausea, vomiting, diarrhea). Invirase (saquinavir, SQV) had relatively low oral bioavailability, so they really had to push the dosage up as high as possible, which meant worse side effects. If none of this sounds like much of a picnic—well, it wasn’t; but it was much better than the status quo ante, especially the sickness and (nearly) uniform fatality part. 

Moreover, while the PIs as a class had a higher genetic barrier to resistance than the NNRTIs or most NRTIs, they nevertheless did succumb to resistance eventually. That situation was remedied by a very fortunate coincidence that was discovered quite by accident. It turned out that ritonavir was a particularly powerful example of something called a cytochrome P450 3A4 inhibitor (abbreviated, by the grace of God, and science, to CYP3A4). That means it blocks the activity of an enzyme that plays a role in the metabolism of drugs in the liver. Somebody somewhere along the way had the very bright idea of using extremely small doses of ritonavir to boost levels of other PIs in the bloodstream. At such low doses, the GI side effects of ritonavir were much less pronounced, while the dose of the other PI could be greatly reduced and yet provide a much higher genetic barrier to resistance. That was a blessing—especially when it meant that folks on Crixivan no longer had to worry about taking their PI three times a day on an empty stomach (no food for two hours before or one hour after a dose); and a curse—increasing the risk of kidney stones for those on Crixivan, for example, as well as increasing the risk and severity of other Crixivan-related side effects such as loss of body hair (more of a problem for bears than for twinks, but still).

Anyway—this is getting a bit long-winded. Suffice it to say that HAART, aka triple-combination therapy, aka the cocktail—revolutionized the treatment of HIV, changing it from a nearly uniform death sentence (“nearly” because there is a very small proportion of people with HIV who manage to control the infection indefinitely without medication, a group called long-term non-progressors or elite non-progressors, who are to this day the subject of intense focus by scientists seeking clues to a cure for HIV) to a chronic, manageable condition (as people often used to say, “like diabetes,” which I think undersells the seriousness and potentially life-threatening nature of diabetes). Today, we take new advances in HIV treatment (and prevention) almost for granted—the advent of pre-exposure prophylaxis (PrEP), the fact that undetectable equals untransmittable, the advent of long-acting drugs such as cabotegravir, promising research into new types of treatment like broadly neutralizing antibodies, and even progress, albeit incremental, towards HIV vaccines (both preventive and therapeutic). But in 1996, the advent of HAART was a virtually unimaginable gift. 

Of course, the international HIV/AIDS community still faces tremendous issues of availability and access to state-of-the-art treatments and prevention strategies, especially in resource-limited countries, among marginalized populations, and particularly among women. We must never lose sight of this reality. At the same time, we can, I think, allow ourselves to be grateful for the fact that we are dealing with issues of access and availability, rather than dealing with the issue of whether or not effective methods of treatment and prevention even exist. I said it at the outset, and I’ll say it again: HIV and AIDS are, though by no means behind us, nevertheless something we more or less know what to do about. What we need now, in this world where we have the right tools, is the political will and the material resources to put those tools into action, not just in wealthy countries or among those who have ready access to healthcare, but for everybody, everywhere in the world. 

And finally… a personal reminiscence. I attended the Vancouver conference in 1996 as part of my job doing continuing medical education programming sponsored by leading academic institutions and funded by unrestricted educational grants from Glaxo. We worked not only with renowned research clinicians like Paul Volberding, Harrold Kessler, Robert “Chip” Schooley, and Mike Saag, but also with leading community-based AIDS advocates and activists. One of these was Moisés Agosto-Rosario, widely acknowledged to be the first person to come out as gay and HIV-positive on the island of Puerto Rico. The company I worked for organized a big bash in honor of Moisés in Vancouver that year. The reason for this celebration of his life and his work was grim: His AIDS was very advanced, and he was presumed to be near death. The party was meant to be a worthy sendoff for a young man who had given his all, and presumably his very life, to the fight against AIDS. 

The reception was held at the incomparably beautiful Museum of Anthropology, on the traditional land of the Musqueam people, with its iconic Great Hall, a spectacular space enclosed within 45-foot-high glass walls. A tented podium was set up on the sprawling grounds behind the museum. A number of friends and colleagues took to the podium to speak about Moisés—his intelligence, his wit, his charm, and his fierce determination to fight AIDS. Finally, it was time for Moisés himself to speak. Up to the podium he strode, this slight, sexy, 35-year-old man whom we had come expecting never to see again. 

But that was not how it was going to go down. Moisés flashed his devilish grin and spoke loud, clear, and strong into that microphone. He was alive, he was well, and he planned to stay that way for a long, long time, continuing this fight, and embarking on new fights for human rights and for racial and social justice. Moisés, it turns out, had been in a clinical trial of one of the groundbreaking new triple-combination HAART regimens (I have no idea which one). Moisés, like so many others, was there to do his best imitation of Lazarus. Moisés had literally risen from his deathbed, like hundreds of others who had participated in clinical trials of the new regimens, and like the thousands of others who would, within days, have access to these new, truly lifesaving treatments. He still works on behalf of all people living with HIV today. He even contributed to an article in this issue. The topic? An HIV cure.

We had come to a party that we expected to be bittersweet. We left a party that was pure magic. 

Michael Broder is a gay, white, poz, Jewish, male, late-Boomer Brooklyn native (b. 1961). Columbia undergrad, MFA in creative writing from NYU, and PhD in classics from the CUNY Graduate Center. He tested HIV-positive in 1990, and started doing AIDS-related journalism while collecting unemployment insurance in 1991. He lives in Bed-Stuy, Brooklyn with numerous houseplants and three feral backyard cats.