When Did HAART Become ART?

Change in terminology is about more than semantics

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Antiretroviral therapy is used to treat HIV and is comprised of a combination of drugs that block different stages in the virus' replication cycle. By doing so, the virus can be suppressed to undetectable levels where it can do the body little harm.

The effectiveness of the combination antiretroviral therapy was first reported by researchers in 1996 at the International AIDS Conference in Vancouver, who dubbed the approach HAART (highly active antiretroviral therapy).

Truvada (tenofovir, emtricitabine)
Justin Sullivan / Getty Images News / Getty Images

Today, the term HAART is less commonly used and has largely been supplanted in the medical literature by the simplified ART (antiretroviral therapy). The change in terminology is about more than just semantics; it reflects a shift in the goals and benefits of HIV therapy and a step away from what HAART historically implied.

Before HAART

When the first cases of HIV were identified in the United States in 1982, scientists rushed to find ways to treat a virus that had little precedent in modern medicine.

It would take five years before the first antiretroviral drug, called AZT (zidovudine), was approved by the Food and Drug Administration (FDA) in March of 1987. It provided the public the first assurance that the disease, largely considered a death sentence, might one day be controlled.

Despite the early breakthrough, AZT only offered modest benefits, increasing survival times by an average of 24 months.

The rapid development of drug resistance rendered the drug increasingly useless, while the drug's toxic effects often left users with severe anemia, liver problems, and other intolerable complications.

By 1988, three other drugs were quickly approved—Hivid (ddC, zalcitabine), Videx (ddI, didanosine), and Zerit (d4T, stavudine)—and used in combination therapies in an effort to further extend life expectancy. And, while they certainly helped, they proved even more toxic than AZT and required complex dosing schedules, often with multiple doses taken throughout the day and night.

What researchers quickly began to realize is that these drugs—and subsequent ones like Viramune (nevirapine) and Epivir (3TC, lamivudine)—failed to achieve durable control because they all had similar mechanisms of action and only blocked one of the seven stages of HIV's replication cycle.

It was proposed that by targeting other stages, the virus would have far less opportunity to replicate and could potentially be fully controlled. That promise began to be realized in 1995 with the introduction of a new class of antiretroviral drugs known as protease inhibitors (PIs).

Advent of HAART

In 1995, the FDA approved the first protease inhibitor, called Invirase (saquinavir). Unlike other antiretrovirals of the time, which blocked the virus' ability to "hijack" a cell's genetic machinery and turn it into an HIV-producing factory, PIs blocked the virus' ability to assemble new copies of itself from structural proteins.

This one-two approach proved to be the turning point in the growing pandemic.

It was reported at the 1996 conference in Vancouver that the strategic use of three drugs from each of the two classes was able to achieve and sustain an undetectable viral load, effectively putting the disease into remission.

The new approach was quickly dubbed HAART and immediately implemented as the standard of care. Within the span of three short years, HIV deaths in the United States and Europe plummeted by more than 50%—the first such downturn since the start of the pandemic.

Even so, HAART was far from perfect, and the average life expectancy, while vastly improved, was still less than that of the general population. By the turn of the century, a 20-year-old on antiretroviral therapy could potentially live to their early 50s.

Within this context, "highly effective" was as indicative of HAART's limitations as its benefits.

Beyond HAART

By 2000, the limitations of the available antiretroviral drugs became increasingly clear. Despite their ability to achieve viral suppression, they could be extremely challenging to the user for several different reasons:

  • Protease inhibitors of the time were associated with potentially severe metabolic effects, including lipodystrophy (the sometimes-disfiguring redistribution of body fat), insulin resistance, and cardiac arrhythmias.
  • AZT, Zerit, and other drugs classified as nucleoside reverse transcriptase inhibitors (NRTIs) could cause severe peripheral neuropathy and potentially life-threatening lactic acidosis.
  • Drugs of the time were less "forgiving" and subject to the rapid development of drug resistance if treatment adherence was anything less than perfect. Some non-nucleoside reverse transcriptase inhibitors (NNRTIs) like Viramune could develop resistance with only a single viral mutation.
  • Some protease inhibitors, like Invirase, required three capsules every 8 hours—a schedule that many found difficult to sustain over the long term.

So problematic were these issues that HAART was standardly delayed until the immune function dropped below a certain threshold (namely, a CD4 count of less than 350). The risks of early treatment at the time were seen to outweigh the benefits.

All of that changed in 2001 with the introduction of Viread (tenofovir disoproxil fumarate), a new type of NRTI that had far fewer side effects, could overcome deep resistance, and only required one pill daily.

By 2005, with life expectancy rates increasing and mortality rates dropping worldwide, researchers were able to show that beginning treatment of HIV at the time of diagnosis prevented severe HIV-associated and non-HIV-associated illnesses by an astonishing 61%.

With universal treatment at diagnosis becoming the new standard worldwide, the medical community began using ART to describe a therapeutic approach that was now more than just "highly effective."

ART Today

The main difference between HAART of the late-1990s/early-2000s and ART today is that HIV can truly be considered a chronic, manageable condition. Not only can a 20-year-old diagnosed with HIV today live well into their 70s, but they can do so with drugs that are safer, longer-lasting, and easier to take.

Newer Drugs and Drug Classes

In recent years, newer classes of antiretroviral drugs have been developed to attack the virus in different ways. Some prevent the attachment of HIV to host cells (entry/attachment inhibitors), while others block the integration of viral coding into the host cell's nucleus (integrase inhibitors).

In addition, newer versions of PIs, NRTIs, and NNRTIs have been created that offer better pharmacokinetics (drug activity), fewer side effects, and better drug resistance profiles.

One such example is an updated version of Viread called tenofovir alafenamide (TAF). Rather than delivering the drug directly, TAF is an inactive "prodrug" that is converted by the body into tenofovir. This cuts the dose from 300 mg to 25 mg with the same clinical results while reducing the risk of kidney problems associated with Viread use.

Fixed-Dose Combination Drugs

Another advancement in therapy is the development of fixed-dose combination (FDC) drugs that can deliver complete therapy with just one pill daily. Today, there are 13 of these all-in-one drugs approved by the FDA.

Single-pill formulations not only improved adherence rates but have been shown to significantly reduce the risk of severe illnesses and hospitalizations compared to multi-pill antiretroviral therapies.

Redefining Combination Therapy

The term HAART has long been synonymous with triple-drug therapy. And, while it is true that ART typically consists of three or more antiretrovirals, improved pharmacokinetics have now made it possible to treat HIV with only two antiretroviral drugs.

In 2019, the FDA approved the first complete two-drug therapy, known as Dovato, which combines a newer-generation integrase inhibitor called dolutegravir with an older NRTI called lamivudine. The combination has proven to be just as effective as standard triple therapy with fewer side effects.

Further turning the definition of ART on its ear was the 2021 release of an injectable therapy known as Cabenuva.

Cabenuva is the first once-monthly therapy able to achieve sustained viral suppression with one injection of the integrase inhibitor cabotegravir and one injection of a newer NNRTI called rilpivirine.

Advances like these redefine what ART means and what it might eventually become.

A Word From Verywell

Although the goals of antiretroviral therapy remain the same, ART today bears only a glancing resemblance to HAART of the past. Without exception, the benefits of treatment far outweigh any concerns about the drugs or their side effects.

Moreover, the benefits extend to those who are not infected. Landmark research published in a 2019 edition of The Lancet concluded that people with HIV who achieve an undetectable viral load have a zero chance of infecting others.

These factors further punctuate the need for HIV testing and illustrate why the U.S. Preventive Services Task Force recommends that all Americans ages 15 to 65 be tested for HIV once as part of a routine doctor's visit.

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