dolutegravir
HIV integrase strand transfer inhibitor· Brands: Tivicay, Triumeq, Juluca, DovatoPO
Mechanism of action
Dolutegravir inhibits HIV integrase by binding to the active site and blocking the strand transfer step of viral DNA integration into the host cell genome, thereby preventing viral replication.
Pharmacokinetics
Dolutegravir is well absorbed after oral administration, with peak plasma concentrations occurring about 2 to 3 hours after dosing. It is highly bound to plasma proteins. Metabolism is mediated by UGT1A1 and CYP3A4. The terminal half-life is approximately 14 hours, supporting once-daily dosing. Elimination is predominantly in the faeces as unchanged drug, with a minor renal component.
Indications & dosing
HIV-1 infection in treatment-naive or treatment-experienced adults
In combination with other antiretrovirals; consider twice daily if integrase inhibitor resistance suspected.
- adult · PO: 50 mg once daily · In combination with other antiretrovirals; consider twice daily if integrase inhibitor resistance suspected.
HIV-1 infection with documented integrase inhibitor resistance (INSTI-resistant)
Twice daily dosing for patients with known INSTI resistance or virologic failure on other INSTIs.
- adult · PO: 50 mg twice daily · Twice daily dosing for patients with known INSTI resistance or virologic failure on other INSTIs.
HIV-1 infection in pediatric patients weighing ≥40 kg
Weight-based dosing for children <40 kg per local guidelines; this dose applies to ≥40 kg.
- pediatric · PO: 50 mg once daily · Weight-based dosing for children <30 kg per local guidelines; this dose applies to ≥30 kg.
Post-exposure prophylaxis (PEP) of HIV-1 infectionoff-label
Used as part of a 28-day regimen with other antiretrovirals; follow local guidelines.
- adult · PO: 50 mg once daily · Used as part of a 28-day regimen with other antiretrovirals; follow local guidelines.
Contraindications & precautions
- Hypersensitivity to dolutegravir or any component
- Concomitant use with dofetilide · Dolutegravir inhibits OCT2, increasing dofetilide concentrations and risk of ventricular arrhythmias.
- Concomitant use with potent inducers of UGT1A1 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin) · May reduce dolutegravir exposure and risk virologic failure; consider alternative or adjusted dose.
- Pregnancy, particularly first trimester · Current data (e.g. the Tsepamo study) have not shown an increased risk of neural tube defects; dolutegravir may be used in pregnancy - seek specialist advice and discuss effective contraception.
- Perform HIV integrase resistance testing before initiation, especially in patients with prior treatment failure.
- Monitor serum creatinine as dolutegravir can cause a benign increase; true renal function may be assessed using cystatin C or other markers.
- Monitor liver function tests, particularly in patients with underlying liver disease or on hepatotoxic drugs.
- In women of childbearing potential, exclude pregnancy before starting and advise effective contraception; consider the risk of neural tube defects.
- If rifampicin is co-administered, increase dolutegravir dose to 50 mg twice daily.
- Monitor for psychiatric symptoms, especially in patients with a history of depression.
Adverse effects
- Headache
- Insomnia
- Nausea
- Diarrhoea
- Increased serum creatinine
- Hepatic injuryserious
- Hypersensitivity reactions including DRESSserious
- Psychiatric symptoms (depression, suicidal ideation)serious
Renal & hepatic adjustment
- Hepatic impairment (mild): No dose adjustment needed
- Hepatic impairment (moderate): No dose adjustment needed
- Hepatic impairment (severe): Not recommended in severe hepatic impairment due to lack of data
Monitoring, pregnancy & toxicity
- Viral load and CD4 count · At baseline and periodically
- Liver function tests · Baseline and if hepatic symptoms develop
- Renal function · Baseline and during treatment
- Signs of hypersensitivity · At each visit
- Neuropsychiatric symptoms · Monitor for mood changes or sleep disturbance
- Pregnancy: Dolutegravir is generally considered safe in pregnancy and is recommended by many guidelines. Data have not confirmed an increased risk of neural tube defects with periconceptional exposure; specialist advice should be sought.
- Toxicity: Hypersensitivity reactions: rash, fever, organ dysfunction · Discontinue dolutegravir immediately and evaluate; do not rechallenge.
- Toxicity: Hepatotoxicity: elevated transaminases · Monitor liver function; discontinue if significant elevation or hepatic symptoms.
- Toxicity: Immune reconstitution inflammatory syndrome (IRIS) · Manage symptomatically; continue antiretroviral therapy unless severe.
- Toxicity: Neuropsychiatric effects: insomnia, anxiety, depression · Assess mental health; consider dose adjustment or alternative ART if severe.
Clinical notes
Absorption is reduced by antacids containing magnesium or aluminium and by calcium or iron supplements; give these 2 hours before or 6 hours after dolutegravir (iron or calcium supplements may be taken together with dolutegravir if taken with food).
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BNF; local formulary