Saidala 24: Integrase strand transfer inhibitor

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral drugs used primarily in the treatment of HIV-1 infection.
They act by blocking the integrase enzyme of HIV, which is essential for viral replication.
Highly effective at rapidly reducing plasma HIV RNA levels, with a high barrier to resistance (particularly newer-generation INSTIs).
Widely used in first-line combination antiretroviral therapy (ART) due to potent efficacy, good tolerability, and favorable drug–drug interaction profiles.

HIV integrase enzyme catalyzes the insertion of HIV DNA (produced by reverse transcription) into the host cell’s genome.
INSTIs bind to the active site of integrase and block the strand transfer step of integration.
Prevents covalent joining of viral DNA ends to host chromosomal DNA.
This halts the formation of a provirus, preventing the production of new viral particles.

First-Generation INSTIs

Raltegravir (RAL) – first approved INSTI (2007); dosed twice daily (once-daily formulation also available).
Elvitegravir (EVG) – given once daily; requires pharmacokinetic boosting (with cobicistat or ritonavir).

Second-Generation INSTIs

Dolutegravir (DTG) – once daily; high barrier to resistance; does not require boosting.
Bictegravir (BIC) – available only in fixed-dose combination tablets; once daily; high barrier to resistance; no boosting needed.
Cabotegravir (CAB) – available as oral lead-in tablets and as long-acting intramuscular injection (monthly or every two months).

Absorption: Rapid oral absorption; food can enhance absorption for some (e.g., EVG).
Distribution: Good tissue penetration, including into lymphoid tissues and genital tract.
Metabolism: Primarily via UGT1A1-mediated glucuronidation (RAL, DTG, CAB) and CYP3A4 metabolism (EVG, BIC partially).
Elimination half-life: Ranges from ~9 hours (RAL) to ~40 days (long-acting CAB).
Drug–drug interaction sensitivity: Chelation with polyvalent cations (e.g., antacids, iron, calcium) reduces absorption.

First-line treatment of HIV-1 infection in combination with at least two other active antiretroviral agents.
Post-exposure prophylaxis (PEP) – dolutegravir or raltegravir used in combination regimens.
Pre-exposure prophylaxis (PrEP) – cabotegravir long-acting IM injection approved in some regions as injectable PrEP for high-risk individuals.

Known hypersensitivity to the active drug or formulation components.
Co-administration with strong inducers of UGT1A1/CYP3A4 (e.g., rifampicin without dose adjustment, carbamazepine, St. John’s wort) unless dosing adjustments are possible.

Common

Less Common but Clinically Relevant

Serious (Rare)

Polyvalent cations (calcium, magnesium, iron, aluminum) – form chelates, reducing absorption; should be separated by dosing time.
Rifampicin – reduces INSTI levels via UGT1A1/CYP3A4 induction; dose adjustment needed (e.g., DTG twice daily).
Anticonvulsants (carbamazepine, phenytoin, phenobarbital) – may lower INSTI levels.
Metformin – dolutegravir increases metformin exposure; dose limitation and monitoring advised.

HIV RNA viral load and CD4 count periodically to assess treatment efficacy.
Liver function tests in patients with viral hepatitis or preexisting liver disease.
Weight and metabolic parameters during long-term use.
Drug–drug interaction risk, especially with cations and enzyme inducers.

First-generation agents (RAL, EVG) have lower resistance barriers compared to newer INSTIs.
EVG requires pharmacokinetic boosting, increasing interaction risk.
Weight gain risk observed in recent studies with newer agents.
Interaction with polyvalent cations requires patient adherence to dosing separation.

Saidala 24