Integrase inhibitors are a class of antiretroviral drugs that work by blocking the HIV integrase enzyme. Integrase is an essential enzyme required by HIV to integrate its genetic material into the DNA of human cells. By blocking this integration process, integrase inhibitors prevent HIV from replicating and spreading further in the body. Three integrase inhibitors have been approved by the FDA for treatment of HIV infection - raltegravir, elvitegravir, and dolutegravir. These drugs play an important role in modern antiretroviral therapy regimens due to their strong antiviral activity and favorable tolerability and resistance profiles.
Mechanism of Action
HIV relies on its Integrase Inhibitors enzyme to insert its own genetic material into the DNA of human cells in order to hijack the cell's replication machinery and produce new copies of the virus. Integrase inhibitors work by binding to the integrase enzyme and blocking this integration process which is essential for the HIV life cycle. Specifically, integrase inhibitors bind to the integrase active site and inhibit the strand transfer reaction where integrase catalyzes the joining of the HIV DNA to the host cell DNA. By preventing this strand transfer, integrase inhibitors effectively block the formation of the provirus from the input viral RNA. Without the ability to integrate, HIV is unable to persist long-term in the infected cell and cannot produce new virions to spread infection further.
Approved Integrase Inhibitors
Raltegravir was the first integrase inhibitor to be approved by the FDA for treatment of HIV in 2007. It demonstrated excellent efficacy in clinical trials at significantly reducing viral load when used in combination antiretroviral therapy. Common side effects include insomnia, nausea and headache. Raltegravir must be taken twice daily. Elvitegravir is another integrase inhibitor which received FDA approval in 2012. It is usually formulated as part of the fixed-dose combination drug Genvoya along with other antiretrovirals. Elvitegravir has a similar side effect and resistance profile to raltegravir. Dolutegravir is the most recent integrase inhibitor to be approved, receiving approval in 2013. It has shown higher genetic barrier to resistance compared to earlier drugs and can be taken with only a single daily dose. Dolutegravir is now commonly used as the preferred integrase inhibitor option in many treatment guidelines due to its advantages of potency, high genetic barrier and favorable dosing schedule and tolerability profile.
Resistance and Cross-Resistance
Like other antiretrovirals that target specific points in the viral life cycle, resistance can emerge if integrase inhibitors are used improperly or in the setting of treatment failure and ongoing viral replication. The Q148 pathway is the most common resistance pathway seen with raltegravir. Resistance frequently involves one or two specific mutations in the integrase gene (INSTI resistance mutations). Most primary INSTI resistance mutations will confer cross-resistance to all approved integrase inhibitors to some degree. However, certain second-line mutations may allow for compromised activity of some later-generation drugs like dolutegravir. Presence of certain resistance mutations at baseline prior to initiation of integrase inhibitor therapy can significantly reduce the antiviral activity of these drugs. It is important to check for resistance when designing new treatment regimens containing integrase inhibitors.
Use in Clinical Practice
Due to their strong antiviral activity and high genetic barrier to resistance, current treatment guidelines recommend integrase inhibitors as preferred members of first-line antiretroviral regimens in treatment-naïve patients. This includes recommendations from the WHO and DHHS. Common first-line regimens include 2 NRTIs paired with an integrase inhibitor such as dolutegravir or bictegravir. Integrase inhibitors also play a key role in suppressing viral replication in patients experiencing treatment failure on other regimens or those with drug-resistant HIV. They are often used as part of complex multidrug salvage regimens in highly treatment experienced patients. Their barrier to resistance makes them ideal partners for other active agents in these difficult treatment situations. integrase inhibitors administered once daily also fit well with adherence in clinical practice.
Newer Developments
Research in integrase inhibitor development continues with several newer agents in clinical trials. Bictegravir is a recent addition to the class which may offer advantages of once daily dosing and low potential for drug-drug interactions. It is formulated with tenofovir alafenamide and emtricitabine as the fixed-dose combination drug Biktarvy which was approved by the FDA in 2018 and recommended as a preferred first-line regimen. Cabotegravir is a long-acting integrase inhibitor formulated for intramuscular injection which is being studied as a monthly or biannual dosing option for HIV treatment and pre-exposure prophylaxis. These kinds of long-acting agents offer potential for higher adherence which could help reduce new HIV transmissions as part of treatment as prevention strategies.
Integrase inhibitors have emerged as important, well-tolerated drugs that are revolutionizing HIV treatment. With their strong antiviral potency and high barrier to resistance, they represent preferred anchor agents in contemporary combination regimens. Their favorable profiles also allow for simplified dosing approaches. Continued research seeks to develop additional integrase inhibitors with even more practical dosing schedules through long-acting formulations. Looking forward, integrase inhibitors will likely continue to play a leading role both in suppressing viral load in infected individuals and reducing new HIV transmissions through effective prevention and treatment strategies.
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