Integrase inhibitors, also known as integrase strand transfer inhibitors (INSTIs), are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but they could be applied to other retroviruses.
The discovery and development of integrase inhibitors led to the first integrase inhibitor approval by the U.S. Food and Drug Administration (FDA) on October 12, 2007, for raltegravir (brand name Isentress). Research results published in the New England Journal of Medicine on July 24, 2008, concluded that "raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks."
Since integrase inhibitors target a distinct step in the retroviral life cycle, they may be taken in combination with other types of HIV drugs to minimize adaptation by the virus. They are also useful in salvage therapy for patients whose virus has mutated and acquired resistance to other drugs.
Drugs in use and under development
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Currently in use
- Dolutegravir, brand name Tivicay, licensed by ViiV Healthcare, was approved by the FDA in 2013 and has recently gained European approval in January 2014. Dolutegravir is marketed as 50 mg tablets as a once or twice daily add on to concurrent HAART therapy.
- Elvitegravir (brand name Vitekta), licensed by Gilead Sciences from Japan Tobacco, after undergoing Phase 3 clinical trials, was approved by the U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination Stribild. Elvitegravir is a low-molecular-weight, highly selective integrase inhibitor that shares the core structure of quinolone antibiotics.
- Raltegravir, brand name Isentress, developed by Merck & Co., was approved by the FDA on October 2007.
- BI 224436
- Bictegravir (GS-9883)
- MK-2048, a second generation integrase inhibitor, that appears to have a duration of action up to four times longer than raltegravir.
- Steigbigel RT, Cooper DA, Kumar PN, et al. (July 2008). "Raltegravir with optimized background therapy for resistant HIV-1 infection". N. Engl. J. Med. 359 (4): 339–54. doi:10.1056/NEJMoa0708975. PMID 18650512.
- Gilead Press Release Phase III Clinical Trial of Elvitegravir July 22, 2008
- AIDSinfo - HIV/AIDS Drug Information - GS 9137 (elvitegravir)
- MK-0518, the first Integrase Inhibitor for HIV
- HIV Antiretroviral Agents in Development
- GS 9137 (elvitegravir) factsheet from NIH
- Savarino A (December 2006). "A historical sketch of the discovery and development of HIV-1 integrase inhibitors". Expert Opin Investig Drugs. 15 (12): 1507–22. doi:10.1517/13543718.104.22.1687. PMID 17107277.
- IntegraseBookFull PDF
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