Integrase Inhibitors: After 10 Years of Experience, Is the Best Yet to Come?

Abstract

The era of the integrase strand transfer inhibitors (INSTIs) for the treatment of human immunodeficiency virus (HIV) infection began with raltegravir in 2007. Since that time, several other INSTIs have been introduced including elvitegravir, dolutegravir, and, most recently, bictegravir, that have shown great utility as part of antiretroviral regimens in both treatment-naive and treatment-experienced patients. At present, antiretroviral guidelines fully endorse the INSTI class as part of all first-line treatment regimens. After 10 years of experience with INSTIs, newer agents are on the horizon such as cabotegravir and MK-2048 for potential use as either HIV pre-exposure prophylaxis or maintenance therapy. This review provides a brief overview of the INSTI class including agents currently available and those still in development, reviews available data from both completed and ongoing clinical trials, and outlines simplification strategies using INSTIs. AUC = area under the curve; CYP = cytochrome P450; DHHS = U.S. Department of Health and Human Services; MATE1 = multidrug and toxin extrusion protein; OCT2 = organic cationic transporter 2; P-gp = P-glycoprotein; S cr = serum creatinine concentration; UGT = uridine diphosphate-glucuronosyltransferase. a Class drug-drug interactions: Integrase strand transfer inhibitor exposures are reduced when administered with polyvalent cation-containing supplements including acid-suppressive therapies and with potent CYP3A4/UGT1A1 inducers (e.g., carbamazepine, phenytoin, and rifamycins). b Stribild contains elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; available only as a single-table formulation. c Genvoya contains elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide; available only as a single-table formulation. d Biktarvy contains bictegravir, emtricitabine, and tenofovir alafenamide; available only as a single-table formulation. EXPERIENCE WITH INTEGRASE INHIBITORS Brooks et al

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

“…Both clinical trials and real-life data have demonstrated the high efficacy, favorable safety profile, tolerability, low toxicity, and relatively high genetic barrier to resistance of INSTIs for both naïve and ART-experienced patients [7][8][9].…”

“…Another INSTI, cabotegravir (CAB), is the newest drug that is being developed as a long-acting injectable for monthly or quarterly administration and as an oral tablet for daily use for the treatment and prevention of HIV-1 infection, and it is currently in the late phase of clinical trials [8,15]. At present, a long-acting regimen with CAB has been approved by Health Canada.…”

How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase

“…Two classes of inhibitors have been developed to inhibit IN functions. INSTIs, such as raltegravir or dolutegravir, inhibit the strand-transfer step catalyzed by IN and are used in antiviral therapies [ 18 ]. ALLINIs induce abnormal IN multimerization, prevent interaction on IN with viral RNA, generating eccentric non-infectious particles defective in viral replication [ 17 , 19 ].…”

“…The primary function of integrase is integration of viral DNA into the host genome. Integrase strand-transfer inhibitors (INSTIs) that target this function have been developed and are used to treat HIV-1 infections [ 18 ]. Recent studies showed that IN is also essential during morphogenesis of the particles [ 17 ].…”

Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis

“…This function has been successfully targeted by a class of antiretrovirals known as integrase strand-transfer inhibitors (INSTIs) [ 3 ]. Four FDA-approved INSTIs, raltegravir [ 4 ], elvitegravir [ 5 ], dolutegravir [ 6 ], and bictegravir [ 7 ], have become key components of anti-retroviral therapy regimens and are both highly effective and well tolerated ([ 8 , 9 , 10 ], reviewed in [ 11 ]). A fifth, cabotegravir [ 12 ], is currently in late stage clinical trials.…”