Dolutegravir

• HIV-1 Infection
• Antiretroviral Therapy
• First-Line HIV Treatment
• Integrase Inhibitor-Based Regimens

Dolutegravir is an integrase strand transfer inhibitor (INSTI) used in the treatment of HIV-1 infection. This second-generation integrase inhibitor offers potent antiretroviral activity, a high genetic barrier to resistance, and minimal drug interactions, making it a cornerstone of many modern HIV treatment regimens.

Mechanism of Action

Dolutegravir inhibits HIV integrase, an enzyme essential for viral replication. During the HIV life cycle, viral RNA is reverse-transcribed into DNA, which must then integrate into the host cell's chromosomal DNA to produce new viral particles. Integrase catalyzes this integration process through two sequential reactions: 3'-processing and strand transfer. Dolutegravir specifically inhibits the strand transfer step by binding to the integrase-DNA complex and blocking integration of viral DNA. The result is prevention of HIV replication. Dolutegravir has a longer dissociation half-life from the integrase-DNA complex compared to first-generation INSTIs, contributing to its high barrier to resistance.

Available Formulations

Dolutegravir is available as film-coated tablets in 10 mg, 25 mg, and 50 mg strengths. It is also available in fixed-dose combination tablets with lamivudine (Dovato), with abacavir and lamivudine (Triumeq), and with rilpivirine (Juluca). A dispersible tablet formulation is available for pediatric patients. The tablets can be taken with or without food.

Medical Uses

Dolutegravir is FDA-approved for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 3 kg, in combination with other antiretroviral agents. It can be used in treatment-naive patients, treatment-experienced INSTI-naive patients, and certain treatment-experienced INSTI-experienced patients. Two-drug regimens with dolutegravir plus lamivudine or rilpivirine are approved for virologically suppressed patients. Dolutegravir-based regimens are recommended as preferred first-line therapy in many guidelines.

Dosing Guidelines

For treatment-naive or treatment-experienced INSTI-naive adults, the dose is 50 mg once daily. For INSTI-experienced patients with certain resistance mutations or when administered with certain inducers (rifampin, carbamazepine), the dose is 50 mg twice daily. Pediatric dosing is weight-based. Dolutegravir should be taken 2 hours before or 6 hours after cation-containing antacids, laxatives, or supplements (calcium, iron, magnesium, aluminum) to avoid reduced absorption.

Important Safety Information

Hypersensitivity reactions, including rash, constitutional symptoms, and organ dysfunction (including liver injury), have been reported. The medication should be discontinued immediately if hypersensitivity is suspected and not restarted. Hepatotoxicity has occurred, particularly in patients with hepatitis B or C coinfection. Immune reconstitution syndrome may occur. There were initial concerns about neural tube defects in infants exposed to dolutegravir at conception, though subsequent data suggest the risk is lower than initially reported. Mental health effects including insomnia, depression, and suicidal ideation have been reported.

Drug Interactions

Dolutegravir levels are reduced by CYP3A and UGT1A1 inducers (rifampin, carbamazepine, phenytoin, St. John's Wort); dose increase to 50 mg twice daily is required with some inducers. Metal cation-containing products significantly reduce absorption; appropriate separation is required. Metformin levels increase with dolutegravir; dose limits apply. Dofetilide is contraindicated due to increased dofetilide levels. Dolutegravir generally has fewer drug interactions than older antiretroviral classes.

Special Populations

Dolutegravir should be used during pregnancy only after careful consideration of risks and benefits. It is one of the preferred INSTIs during pregnancy when initiated after 6 weeks of conception. It is present in breast milk; in the US, breastfeeding is not recommended for HIV-infected women. Safety and efficacy have been established in pediatric patients weighing at least 3 kg. Elderly patients do not require dose adjustment. No dose adjustment is needed for renal impairment. Use with caution in severe hepatic impairment; limited data exist.