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Integrase inhibitors (INIs) 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 have been applied to other retroviruses.[verification needed] The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as integrase binding inhibitors (INBIs), are still experimental.
The development of integrase inhibitors led to a first approval for the class by the U.S. Food and Drug Administration (FDA) on October 12, 2007, for raltegravir (brand name Isentress). Research published at the time supported the conclusion 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
Currently in use
- Raltegravir, brand name Isentress, developed by Merck & Co., was the first INSTI approved by the FDA on October 2007. Two formulations of raltegravir are currently available: 400 mg tablets (one tablet twice daily) and 600 mg tablets (two tablets once daily).
- On August 27, 2012, following a successful Phase 3 clinical trial, Elvitegravir (brand name Vitekta), licensed by Gilead Sciences from Japan Tobacco, was approved by the U.S. Food and Drug Administration for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination with emtricitabine and tenofovir disoproxil (Stribild). Elvitegravir is a low-molecular-weight, highly selective integrase inhibitor that shares a core structure with quinolone antibiotics. A similar fixed dose combination containing tenofovir alafenamide instead of tenofovir disoproxil is offered under the brand name Genvoya. In every case, elvitegravir is given together with the "booster"[clarification needed] cobicistat (also a part of the fixed combinations drugs, Stribild and Genvoya). Boostering[clarification needed] of elvitegravir with cobicistat is similar to that of protease inhibitors by ritonavir.[according to whom?]
- 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 in a combination ART therapy together with two NRTIs. One dose daily is often sufficient, though in cases of viral resistance, a twice dose daily regimen—taken together with food, to further increase bioavailability—is recommended. A fixed combination therapy of dolutegravir with the NRTIs abacavir and lamivudine is available under the brand name Triumeq, a one-pill, once-daily complete ART regimen.
- Bictegravir, known as GS-9883 while being brought forward by Gilead Sciences. The combination drug bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy), produced by Gilead Sciences, was approved for use in the United States in 2018.[better source needed]
- Cabotegravir, developed by ViiV Healthcare, was approved in conjunction with rilpivirine by the FDA in January 2021 as a once-monthly injection for the treatment of HIV.
- BI 224436
- MK-2048, a second generation integrase inhibitor, that appears to have a duration of action up to four times longer than raltegravir.
- "FDA approval of Isentress (raltegravir)". U.S. Food and Drug Administration. October 12, 2007. Archived from the original on January 12, 2017. Retrieved October 8, 2019.
- 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. S2CID 17257548.
- USA (2014). "Antiretroviral Therapy: Current Drugs". Infectious Disease Clinics of North America. Ncbi.nlm.nih.gov. 28 (3): 371–402. doi:10.1016/j.idc.2014.06.001. PMC 4143801. PMID 25151562.
- "Gilead Initiates Phase III Clinical Trial of Elvitegravir, an Investigational Integrase Inhibitor for HIV" (Press release). Archived from the original on 2013-02-08. Retrieved 2010-06-25.
- "Elvitegravir". AIDSinfo. National Institutes of Health. Archived from the original on 2011-09-27. Retrieved 2007-10-13.
- "U.S. Food and Drug Administration Approves Gilead's Biktarvy (Bictegravir, Emtricitabine, Tenofovir Alafenamide) for Treatment of HIV-1 Infection" (Press release). Gilead. February 7, 2018.
- MK-0518, the First Integrase Inhibitor for HIV, No Blarney
- HIV Antiretroviral Agents in Development
- GS 9137 (elvitegravir) fact sheet 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:10.1517/135437220.127.116.117. PMID 17107277. S2CID 207475472.
- IntegraseBookFull (PDF)
- integrase+inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)