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 they could be applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established use. Other classes, such as integrase binding inhibitors (INBIs), are still experimental.
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
This section needs to be updated.June 2013)(
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 in a combination ART therapy together with two NRTIs. Oftentimes one dose daily is sufficient; except in case of viral resistance then a twice dose daily regimen together with food, which further increases the bioavailability, is recommended. Furthermore, a fixed combination of dolutegravir together with the NRTIs abacavir and lamivudine is available under the brand name Triumeq. This tablet contains a full ART building a complete one-pill once-daily regimen.
- 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 with emtricitabine and tenofovir disoproxil (Stribild). 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 cobicistat, which is also part of the fixed combinations Stribild and Genvoya. Boostering of elvitegravir with cobicistat is similar to the boostering of protease inhibitors by ritonavir. 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 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). Fixed combinations are not available.
- Bictegravir, (INN; formerly known as GS-9883) The combination drug bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy), produced by Gilead Sciences, was approved for use in the United States in 2018.
- BI 224436
- 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:10.1517/135437220.127.116.117. PMID 17107277.
- IntegraseBookFull PDF