How HAART (Highly Active Antiretroviral Therapy) Works

The Triple Therapy That Turned the HIV Epidemic Around

HAART is the acronym for "highly active antiretroviral therapy," a term coined in the late 1990s to describe the effectiveness of combination drug therapies used to treat HIV.

Prior to HAART, the use of one or two antiretroviral drugs had generally limited success in patients with HIV, resulting in rapid treatment failure as well as the inability to fully suppress viral activity.

3 pill bottles of antiretrovirals
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It was with the introduction of protease inhibitors in 1996 that doctors were able to combine three or more drug agents in a way that effectively stopped HIV from replicating at different points in its life cycle. With the advent of HAART, doctors and scientists were able to witness a startling 50% drop in the number of AIDS-related deaths in the U.S. and Europe in the span of three short years (1995-1999).

In addition to HAART, the multi-drug approach was also popularly known as "triple therapy" or a "triple drug cocktail."

Today, the term has largely been supplanted by other monikers, including cART (combination antiretroviral therapy) or, even more simply, ART (antiretroviral therapy).

How HAART Works

As opposed to single-drug or dual-drug therapies, the combination of three or more antiretroviral can work as a tag team, effectively suppressing a wide variety of HIV that can exist within a single viral population. If one drug is unable to suppress a certain viral type, one or both of the other agents would be more than likely to do so.

By keeping the viral population fully suppressed (undetectable), there are fewer circulating viruses in the bloodstream and fewer opportunities for the virus to mutate into a drug-resistant strain.

This is why pre-HAART therapies tended to fail so quickly: Smaller mutant populations were allowed to persist and eventually increase in number to become the predominant viral strain. When this happens, the drugs are no longer able to stop HIV from replicating, a condition which is described as "drug resistance."

There are currently five classes of antiretroviral drug, each of which inhibits a specific stage in the HIV life cycle:

  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  • Nucleoside reverse transcriptase inhibitors (NRTIs)
  • Protease inhibitors (PIs)
  • Fusion inhibitors
  • CCR5 antagonists
  • Integrase strand transfer inhibitors (INSTIs)
  • Post-attachment inhibitors

Other classes of antiretrovirals are being investigated, while newer-generation drugs aim to improve tolerability, reduce adverse effects and simplify dosing for those on therapy.

Future of HAART

In addition to providing durable suppression of HIV in infected individuals, HAART is now being used as a means to reverse infection rates in many high-risk populations. The strategy, known as treatment as prevention (TasP), has been shown to reduce the "community viral load" within a population, making it much more difficult to pass the virus from an infected person to a non-infected person.

On an individual level, TASP can reduce the risk of transmission to zero if you have a fully undetectable viral load, according to the landmark PARTNER1 and PARTNER2 studies.

Moreover, HAART has been shown to reduce the risk of both HIV- and non-HIV-related illnesses (including cancers and heart disease) by as much as 58% if started at the time of diagnosis. As a result, it is now recommended that HAART be initiated in all persons with HIV, irrespective of immune status, income, geographic region, race, or HIV viral load.

The concept of HAART is also likely to change with the development of long-lasting antiretroviral drug agents (potentially allowing for monthly or quarterly injections) and next-generation drugs which aim to lower the traditional triple-drug cocktail to as few as two drugs.

On April 8, 2019, the U.S. Food and Drug Administration issued the approval of the first two-drug combination called Dovato (dolutegravir and lamivudine) that works just as effectively for people newly treated for HIV.

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  6. U.S. Food and Drug Administration. FDA approves first two-drug complete regimen for HIV-infected patients who have never received antiretroviral treatment. Published on April 8, 2019.

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