What Are Integrase Inhibitors?

Class of DrugUnds Listed Among Preferred First-Line Options in the U.S.

Courtesy Gilead Sciences

Integrase inhibitors (also known as integrase strand transfer inhibitors, or INSTIs) are a powerful class of antiretroviral drug which prevents HIV from integrating its genetic coding (genome) into the DNA of the infected host cell. It does so by blocking an enzyme called integrase and, by doing so, makes it impossible for HIV to replicate.

Isentress (ratelgravir) was the first INSTI approved by the U.S.

Food and Drug Administration (FDA) on October 12, 2007. All told, there are currently three approved INSTI drug molecules and four fixed dose combination drugs in which an INSTI is a component

Drug manufacturers ViiV and Janssen Pharmaceuticals are currently collaborating on another combination drug which would combine dolutegravir with the drug Edurant (rilpilvirine). Another promising INSTI candidate, cabotegravir, is undergoing Phase III human trials.

As a class of drugs, integrase inhibitors are considered advantageous in treating HIV infection, with easier dosing requirements, lower side effects, improved resistance profiles, and greater durability.

As such, INSTIs are classified as among the preferred treatment options in many HIV guidelines, including those of the U.S.

How Do Intergrase Inhibitors Work?

HIV integrates its viral genome into the host cell's DNA in a five-step process:

  1. The integrase enzyme binds to HIV DNA, the latter of which is created in a process called reverse transcription.
     
  1. The HIV DNA is then prepared for integration in a process called cleaving, which literally cleaves the viral genetic strand, leaving open gaps in its structure.
     
  2. The cleaved strand is then inserted into the host cell's nucleus through a nuclear pore.
     
  3. Once inside the nucleus, the HIV DNA is transferred into the host DNA in is what's called a strand transfer reaction. In this stage, the viral DNA the literally attacks the host cell's DNA, separating the bonds that hold the host DNA together and attaching itself through the chemical gaps in the viral DNA strand.
     
  4. The attack then incites a natural protective response called gap repair, in which the host cell will automatically repair any damage to the DNA, essentially facilitating the takeover of its genetic coding.

Simply by blocking the integrase enzyme, the entire integration process is stopped, effectively ending the virus' life cycle. However, as integration is only one of several stages of the HIV life cycles, other drugs are taken to inhibit other stages, further preventing HIV from replicating and ensuring that viral activity is fully suppressed (as measured by the HIV viral load).

Sources:

U.S. Food and Drug Administration (FDA). "Drug Approval Package – Drug Name: Isentress (ratelgravir) 400mg Tablets." Silver Spring, Maryland; October 12, 2007.

U.S. National Library of Medicine. "TIVICAY (dolutegravir sodium) tablet, film coated." Bethesda, Maryland; revised August 2013.

FDA. "VITEKTA - FULL PRESCRIBING INFORMATION." Accessed February 3, 2015.

ViiV Healthcare. "ViiV Healthcare receives FDA approval for Triumeq." London, England; press release issued 22 August 2014.

FDA. "FDA approves new combination pill for HIV treatment for some patients." Press release issued on August 27, 2012.

FDA. "FDA approves new treatment for HIV." Press release issued on November 5, 2015.

National Institute of Allergies and Infectious Diseases (NIAID) "HIV/AIDS Preclinical Drug Development." Bethesda, Maryland; updated July 21, 2015.

Department of Health and Human Services (DHHS). "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents." Rockville, Maryland; accessed February 15, 2016.

Craigie, R. and Bushman, F. "HIV DNA Integration." Cold Spring Harbor Perspectives in Medicine. July 2012; 2(7):a006890.

Bushman, F.; Fujiwara, D.; and Craigie, R. "Retroviral DNA integration directed by HIV integration protein in vitro." Science. September 28, 1990; 249(4976):1555-1558.

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