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HAART (Highly Active Antiretroviral Therapy) For Treating HIV

The discovery of HIV in 1981 brought along with it a variety of drug therapies. 'One drug therapy' was initially used to treat people living with AIDS. The most common drug used in the early days was AZT. Although it was initially successful, such form of 'monotherapies' was ultimately found to be ineffective in slowing down the progression of the AIDS-causing virus [1] .

The failure of monotherapies was attributed to the fact that HIV had the ability to quickly create resistance to single-drug treatments. HIV was able to mutate into a form wherein it stopped responding to the individual drugs being administered [2] .

HIV

A combination drug treatment was discovered in 1995. This was known as 'AIDS cocktail'. This therapy was later renamed and is now known as 'Highly Active Antiretroviral Therapy (HAART). It is sometimes also called Combination Antiretroviral Therapy (cART) or simply Antiretroviral Therapy (ART) [3] .

HAART has shown dramatic improvements in the life of people with AIDS. There has been a decrease in the amount of HIV in the body with the use of this treatment. Studies also show an increase in the count of CD4 cells (immune cells that HIV destroys) [4] .

Read on to know more about the life-changing treatment called HAART.

What Is HAART?

HAART is the acronym for 'Highly Active Antiretroviral Therapy'. The term was coined in the late 1990s, keeping in mind the effectiveness of this combination drug therapy in treating HIV [5].

In 1996, with the introduction of protease inhibitors [6] , doctors combined three or more drug agents in such a way that it could successfully stop HIV from replicating at different points in its life cycle. Studies show that with the use of HAART, a startling 50 per cent reduction in AIDS-related deaths were observed [7] .

HAART is also popularly known as 'triple therapy' and 'triple drug cocktail'. This therapy is a customized combination of different medicine classes that a doctor ideally prescribes considering factors such as patient's viral load (amount of virus in the blood), the CD4+ cell count, the particular strain of the virus, etc. However, one should note that HAART cannot get rid of HIV from one's body, and therefore it must be taken by the patient for the rest of his or her life [8] .

HAART basically aims at controlling the viral load and delays/prevents the onset of symptoms and the progression to AIDS. It, therefore, is able to prolong the survival of the people who are infected with HIV.

HAART is known to have effectively managed this ailment which was once concluded as a fatal condition.

How Is HIV Detected?

When a person has contracted HIV, the immune system starts producing antibodies that are nothing but proteins which recognize the virus. The tests conducted to diagnose HIV are basically tests that detect the presence of these antibodies. A brief period of about 6 to 8 weeks after being exposed to the virus is required for the tests to detect and give results accurately.

Although many new test methodologies claim that it can be reduced to a window of just 2 weeks [9] . This waiting period (before tests start showing positive results) is believed to be the most complex and dangerous for HIV transmission. This is so because the chances of a false negative test result are high during this period and yet the person might be highly infectious (spreading the virus rapidly through unsafe actions). The Centers for Disease Control and Prevention (CDC) has now recommended the inclusion of HIV testing as a part of routine medical care for anyone between 13 and 64 years of age [10] .

How HAART Works

Unlike the single-drug or drug-drug therapies, the combination of three or more antiretroviral (as in HAART) drugs are capable of effectively suppressing a wide range of HIV that might be present in a single viral population. When three or more drugs are combined, even if one drug is unable to suppress a particular kind of viral type then the other drug agents come into action [11] .

When the viral population is kept suppressed (not detectable), then there would only be few circulating viruses in the bloodstream and hence fewer opportunities for the virus to mutate into a resistance strain [12] .

This approach of HAART therapy is what became the foundation of its success, unlike the pre-HAART therapies. The therapies that were deployed prior to HAART failed because smaller mutant population were permitted to persist. This eventually increased in number and became the predominant viral strain. When this happened, the drugs were no longer able to stop HIV from replicating [13] (a condition referred to as 'drug resistant')

HIV

Drugs Used In HAART

At present, there are five classes of antiretroviral drugs. Each drug is responsible for suppressing a specific stage in the life cycle of HIV. The five classes are as follows [14] :

Entry or fusion inhibitors (includes CCR5 receptor antagonists)

  • These inhibitors are designed to prevent the virus from entering the CD4 cells.

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI/NtRTI)

  • For HIV to replicate, it requires an enzyme known as reverse transcriptase (RT) [15] . NRTIs blocks the virus's ability to replicate by offering faulty versions of RT to the viruses.

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

  • These work by disabling a key protein which HIV requires to replicate

Integrase inhibitors (INSTI)

  • When HIV enters the CD4 cells, it inserts genetic material into the cells. This insertion is made possible due to the assistance provided by a protein called integrase [16] . The INSTIs are designed to block the virus's ability to complete the replication step.

Protease inhibitors (PI)

  • A protein called protease [17] (key building block that is essential for HIV to replicate) is disabled by this inhibitor.

Investigations are underway for other classes of antiretrovirals. The newer generation drugs are being developed with the aim to improve tolerability, simplify dosing for those on therapy and reduce adverse effects [18] .

HIV

Recommended HIV Treatment Protocol

Going by what the National Institutes of Health suggests, the current recommended dosage for initial HIV drug regimen includes three HIV medicines from two or more different classes of drugs. It usually is of the following kind [19] :

  • Two NRTIs along with an INSTI, NNRTI or PI
  • cobicistat or ritonavir as a booster

Once put on a regimen, it is the responsibility of the doctor to thoroughly monitor the patient and keep a check on the ongoing reaction and success levels. If the regimen does not seem to work or in case the patient starts to show allergic reactions/side effects, then the healthcare provider would need to make changes to the drug regimen.

All people living with HIV are recommended antiretroviral treatment. However, in some cases, receiving treatment is more of an emergency. Such situations could be when [20] :

  • the person is pregnant [21]
  • the person has previously experienced HIV-related dementia or cancer (including other HIV-related complications such as nerve pain or infection)
  • the person has had CD4 counts that are below 200 cells/mm3 [22]
  • the person has hepatitis B or hepatitis C

Continuing antiretroviral treatment life long ensures a low viral load and normal CD4 count, thus ensuring the longer survival of a person infected with HIV [23] .

The Future Of HAART

Apart from just being used as a form of suppression for individuals infected with HIV, HAART is also finding use in being deployed for the reversal of infection rates in the high-risk population. This strategy is termed as 'Treatment as Prevention (TasP)' [24] . Studies have shown that this strategy is quite effective in reducing the 'community viral load' within a particular population. This has made it difficult for the virus to be passed on from an infected person to a non-infected person.

Moreover, research is being widely conducted to determine the effectiveness of HAART in not just reducing risks of HIV, but also that of non-HIV-related illnesses, such as heart diseases and cancer. Medical experts recommend that HAART is initiated in all persons with HIV, irrespective of the geographic region, race, HIV viral load, immune status or income.

The concept of HAART is going to be further modified with the introduction of long-lasting antiretroviral drug agents (which would facilitate monthly or quarterly injections) and next-generation drugs [25] . The aim of these newly developed drugs would be to lower the traditional triple-drug cocktail to fewer drugs (maybe just two).

View Article References
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  2. [2] Heredia, A., Hassounah, S., Medina-Moreno, S., Zapata, J. C., Le, N. M., Han, Y., Foulke, J. S., Davis, C., Bryant, J., Redfield, R. R., … Wainberg, M. A. (2017). Monotherapy with either dolutegravir or raltegravir fails to durably suppress HIV viraemia in humanized mice. The Journal of antimicrobial chemotherapy, 72(9), 2570-2573.
  3. [3] Heredia, A., Hassounah, S., Medina-Moreno, S., Zapata, J. C., Le, N. M., Han, Y., Foulke, J. S., Davis, C., Bryant, J., Redfield, R. R., … Wainberg, M. A. (2017). Monotherapy with either dolutegravir or raltegravir fails to durably suppress HIV viraemia in humanized mice. The Journal of antimicrobial chemotherapy, 72(9), 2570-2573.
  4. [4] Lifson, A. R., Krantz, E. M., Eberly, L. E., Dolan, M. J., Marconi, V. C., Weintrob, A. C., Crum-Cianflone, N. F., Ganesan, A., Grambsch, P. L., Agan, B. K., Infectious Disease Clinical Research Program (IDCRP) HIV Working Group (2011). Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort. AIDS research and therapy, 8(1), 2.
  5. [5] Delaney M. (2006). History of HAART – the true story of how effective multi-drug therapy was developed for treatment of HIV disease. Retrovirology, 3(Suppl 1), S6.
  6. [6] Lv, Z., Chu, Y., & Wang, Y. (2015). HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV/AIDS (Auckland, N.Z.), 7, 95-104.
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  9. [9] Fearon M. (2005). The laboratory diagnosis of HIV infections. The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale, 16(1), 26-30.
  10. [10] Sands A. Diagnostics for HIV diagnosis. In: Consolidated Guidelines on HIV Testing Services: 5Cs: Consent, Confidentiality, Counselling, Correct Results and Connection 2015. Geneva: World Health Organization; 2015 Jul. ANNEX 7.
  11. [11] El Bouzidi, K., Collier, D., Nastouli, E., Copas, A. J., Miller, R. F., & Gupta, R. K. (2016). Virological efficacy of PI monotherapy for HIV-1 in clinical practice. The Journal of antimicrobial chemotherapy, 71(11), 3228-3234.
  12. [12] Sánchez, M. S., Grant, R. M., Porco, T. C., & Getz, W. M. (2006). HIV drug-resistant strains as epidemiologic sentinels. Emerging infectious diseases, 12(2), 191-197.
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  14. [14] Kemnic TR, Gulick PG. HIV, Antiretroviral Therapy. [Updated 2018 Oct 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-.
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Read more about: hiv aids therapy virus drug immune cells
Story first published: Tuesday, March 5, 2019, 12:35 [IST]
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