What class of antiretroviral is Dolutegravir?

Dolutegravir Drug Classification

Dolutegravir is an integrase strand transfer inhibitor (INSTI), specifically a second-generation INSTI approved by the FDA in 2013 for the treatment of HIV-1 infection. 1, 2

Mechanism of Action

• Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle 2
• The drug exhibits potent antiviral activity with IC₅₀ values of 2.7 nM and 12.6 nM in strand transfer biochemical assays using purified HIV-1 integrase 2
• In cell culture, dolutegravir demonstrated mean EC₅₀ values of 0.5 nM to 2.1 nM against wild-type HIV-1 laboratory strains 2

Second-Generation INSTI Characteristics

Dolutegravir is distinguished from first-generation INSTIs (raltegravir and elvitegravir) by several key advantages: 1, 3

• Higher genetic barrier to resistance: The drug's binding potential and half-life at the integrase site are far superior to raltegravir and elvitegravir, conferring unique resistance characteristics 3, 4
• Once-daily dosing capability: The terminal elimination half-life of 13-14 hours allows for once-daily administration without pharmacokinetic boosting 1, 5, 4
• Retained activity against resistant viruses: Dolutegravir maintains in vitro activity against viruses with one or more integrase mutations that confer resistance to first-generation INSTIs 3, 4
• Low risk of resistance development: Clinical trials showed minimal emergence of resistance mutations with virologic failure in INSTI-naïve patients 1, 2

Clinical Positioning

• Dolutegravir demonstrated superiority to both efavirenz and darunavir/ritonavir in treatment-naïve patients, and superiority to raltegravir in treatment-experienced patients 1, 5
• The drug is available as a single agent (allowing flexible combination with other antiretrovirals) or coformulated with abacavir/lamivudine 1
• Twice-daily dosing (50 mg every 12 hours) is required when coadministered with metabolic inducers such as efavirenz, rifampin, or carbamazepine, or in patients with INSTI-associated resistance mutations 1, 2, 5

Important Pharmacologic Distinctions

• Minimal drug interactions: Dolutegravir is metabolized primarily by UGT1A1 with minor contribution from CYP3A4, and does not induce or inhibit major CYP enzymes 2, 3
• No boosting required: Unlike elvitegravir which requires cobicistat boosting, dolutegravir achieves adequate plasma concentrations without pharmacokinetic enhancement 1
• Creatinine elevation without nephrotoxicity: Dolutegravir inhibits renal tubular secretion of creatinine via OCT2, causing benign increases of 0.1-0.15 mg/dL without affecting actual glomerular filtration rate 1, 2, 3