What Is HAART (Highly Active Antiretroviral Therapy)?

How Triple Therapy Turned the HIV Epidemic Around

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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.

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 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 suppress 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 agent would be more than likely to do so.

In turn, by keeping the viral population suppressed (undetectable), there are few circulating viruses in the bloodstream and few opportunities for the virus to mutate into a resistance strain.

It 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 are able to stop HIV from replicating, a condition which we describe as being "drug resistant."

Drugs Used in HAART

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

  • entry or fusion inhibitors (which include CCR5 receptor antagonists)
  • nucleoside and nucleotide reverse transcriptase inhibitors (NRTI/NtRTI)
  • non-nucleoside reverse transcriptase inhibitors (NNRTI)
  • integrase inhibitors
  • protease 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.

The 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.

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.

Two large Phase III trials, called the SWORD-1 and SWORD-2, demonstrated that the use of Tivicay (dolutegravir) and Edurant (rilpivirine) resulted in sustained viral suppression for 48 weeks with minimal side effects. Another smaller trial, called the LAMIDOL study, showed that Tivicay used with lamivudine (an older generation drug) had the potential to achieve the same results in previously treated patients.

Sources:

Sansone, G. and Frengley, J. "Impact of HAART on Causes of Death of Persons with Late-Stage AIDS." Journal of Urban Health. June 2000; 77(2):166-75.

Cohen, M.; Chen, Y.; McCauley, M.; et al. "Prevention of HIV-1 infection with early antiretroviral therapy." New England Journal of Medicine. August 11, 2011; 365(6):493-505.

The INSIGHT START Study Group. "Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection." New England Journal of Medicine. July 20, 2015; DOI: 10.1056/NEJMoa1506816.

Llibre, J.; Hung, C.; Brinson, C.; et al. "Phase III SWORD 1&2: switch to DTG+RPV maintains virologic suppression through 48 wks." 2017 Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle; abstract 44LB

Joly, V.; Burdet, C.; Landman, R.; et al. "Promising results of dolutegravir + lamivudine maintenance in ANRS 167 LAMIDOL trial." 2017 Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle; abstract 458.

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