Dolutegravir – Antiretroviral Therapy

Dolutegravir is a second-generation antiretroviral agent belonging to the class of HIV-1 integrase strand transfer inhibitors (INSTIs). The drug is one of the most modern and effective components of highly active antiretroviral therapy (HAART), characterized by a high genetic barrier to the development of resistance and a favorable safety profile.

The mechanism of action of dolutegravir involves blocking the integrase enzyme, which is essential for the human immunodeficiency virus to incorporate viral DNA into the genetic apparatus of the host cell (CD4+ T-lymphocyte). The drug binds to the enzyme's active site and prevents the strand transfer step, thereby completely interrupting the viral replication cycle. This leads to a rapid and sustained reduction of plasma viral load to undetectable levels.

Dolutegravir is characterized by a long half-life, allowing for once-daily dosing. Due to its structural design, it maintains activity against HIV strains resistant to first-generation integrase inhibitors (such as raltegravir), making it an indispensable tool for treating both treatment-naive and treatment-experienced patients.

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Indications

Dolutegravir is used as part of combination antiretroviral therapy for the treatment of HIV infection:

HIV-1 infection in adults: treatment of patients who have not previously received therapy (naive) and treatment-experienced patients.
HIV-1 infection in adolescents and children: approved for use in children weighing at least 3 kg (in specific dosage forms).
Resistant forms of HIV: therapy for patients with identified partial resistance to other classes of antiretroviral drugs.
Post-exposure prophylaxis (PEP): can be used in emergency prophylaxis regimens following potential exposure to HIV.

Dosage and administration

The dolutegravir administration regimen is standardized, though dosage may be adjusted based on the patient's treatment history.

Standard Dosage: 50 mg (one tablet) once daily for patients without prior exposure to integrase inhibitors.
In Case of Resistance: for patients with confirmed or suspected resistance to INSTIs, the dose is increased to 50 mg twice daily.
Administration Rules: the drug can be taken with or without food. However, when co-administered with etravirine, dolutegravir must be taken with food.
Drug Interactions: medications containing cations (magnesium/aluminum antacids, calcium, iron, multivitamins) should be taken 2 hours before or 6 hours after dolutegravir, as they reduce its absorption.
Missed Dose: if more than 12 hours remain until the next dose, the missed dose should be taken immediately. If less than 12 hours remain, the missed dose should be skipped.

The use of dolutegravir is contraindicated or requires caution in the following cases:

Hypersensitivity: individual intolerance to dolutegravir or any component of the tablet.
Co-administration with Dofetilide: dolutegravir increases dofetilide concentrations, which may cause life-threatening arrhythmias.
Severe Hepatic Impairment: (Child-Pugh Class C), as safety data in this group are limited.
Pregnancy and Planning: requires discussion with a physician (concerns regarding neural tube defects were raised previously, but current data support its use with proper precautions).

Dolutegravir is generally very well tolerated, but the following adverse reactions may occur:

Neurological Symptoms: insomnia (most common), headache, abnormal dreams, dizziness.
Gastrointestinal Tract: nausea, diarrhea, abdominal pain, flatulence.
Psychological Sphere: depression, anxiety (predominantly in patients with a history of mental health disorders).
Laboratory Parameters: slight increase in serum creatinine (not affecting renal function) and elevated creatine phosphokinase (CPK) levels.
Allergic Reactions: very rarely, hypersensitivity reactions with rash and liver function impairment.

Frequently Asked Questions

Dolutegravir is an antiretroviral agent belonging to the class of second-generation integrase strand transfer inhibitors (INSTIs). It works by blocking the integrase enzyme, which the human immunodeficiency virus (HIV) needs to insert its genetic material into human cell DNA. This effectively halts the viral replication process within the body.

Dolutegravir has a high "genetic barrier" to resistance, meaning it is much harder for the virus to mutate and become resistant to this agent. It is also generally better tolerated by patients, causes fewer gastrointestinal and neurological side effects, and requires only once-daily dosing (50 mg).

Dolutegravir can bind with polyvalent metal cations (such as magnesium, aluminum, calcium, or iron) found in antacids and multivitamin supplements. This interaction significantly reduces the absorption of the active substance. Dolutegravir should be taken 2 hours before or 6 hours after taking these supplements.

Currently, dolutegravir is considered safe for use during all stages, including the first trimester of pregnancy. However, before starting therapy or when planning conception, women should consult their healthcare provider to discuss the individual benefits and risks of maintaining their ART regimen.

Some patients using integrase inhibitors, including dolutegravir, have experienced weight gain. In rarer cases, a slight increase in blood glucose levels may occur. It is recommended to monitor your weight and maintain a balanced diet while undergoing therapy.