Introduction 

• Integrase inhibitors (INIs) are a class of antiretroviral drugs that block the action of the HIV integrase enzyme, which is responsible for inserting the viral DNA into the host cell's genome. 

• This step is crucial for viral replication, so inhibiting integrase prevents the virus from spreading further in the body.

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• The first integrase inhibitor, raltegravir (Isentress), was approved by the FDA in 2007, marking a significant advancement in HIV treatment. Raltegravir and other integrase strand transfer inhibitors (INSTIs) target the strand transfer step of integration, effectively suppressing viral replication and are often used in combination with other HIV drugs to reduce resistance.

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• Integrase inhibitors have become a key component of antiretroviral therapy (ART) due to their potency, relatively favorable side effect profile, and ability to work against viruses resistant to other drug classes. 

• Newer generations of integrase inhibitors continue to be developed to overcome resistance and improve dosing convenience. 

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                   IIIustrated mechanism of action             

• Examples of Medication Brand Names (with Images)

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                                      Indication

Integrase inhibitors are primarily indicated for the treatment of HIV infection in adults and children.

 They are used as part of combination antiretroviral therapy (ART) to suppress HIV replication by blocking the viral integrase enzyme, preventing viral DNA integration into host cells. 

First-line regimens often include second-generation integrase strand transfer inhibitors (INSTIs) such as bictegravir and dolutegravir due to their high barrier to resistance and efficacy.

 Additionally, long-acting injectable cabotegravir combined with rilpivirine is approved for maintenance therapy in virally suppressed patients and for pre-exposure prophylaxis (PrEP) to prevent HIV infection in high-risk individuals.

                                     Side Effects

• Common side effects of integrase inhibitors (INSTIs) include

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•  ● neuropsychiatric symptoms such as:

• insomnia, headache, anxiety, depression, dizziness, and mood changes, with dolutegravir (DTG) bearing the highest burden of these effects. 

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• ●Weight gain has been reported with all INSTIs, especially DTG, and may be more pronounced in women and non-white patients. 

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• ●Mild increases in creatinine levels are common but usually not clinically significant. 

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• ●Gastrointestinal symptoms like nausea, diarrhea, and vomiting can also occur.

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• ● Less commonly, serious skin reactions and injection-site reactions (notably with cabotegravir) have been reported.

                    Precautions & Contraindication

Use of certain CYP3A4 inducers (e.g., rifampin, rifabutin, carbamazepine, phenytoin, St. John’s wort) is contraindicated with some INSTIs like bictegravir and elvitegravir, as they reduce drug levels and risk virologic failure.

Co-administration with dofetilide is contraindicated with bictegravir due to increased risk of toxicity.

Elvitegravir is contraindicated with drugs extensively metabolized by CYP3A4 due to severe side effects.

Precautions:

Use caution in patients with low kidney function (eGFR <30 ml/min) or those on other nephrotoxic drugs, as INSTIs can mildly increase creatinine levels without affecting actual kidney function.

Avoid dolutegravir (DTG) in women of childbearing age without effective contraception due to risk of neural tube defects if taken peri-conception.

Monitor neuropsychiatric symptoms closely, especially with dolutegravir, in patients with a history of severe psychiatric illness.

Weight gain is a noted side effect with all INSTIs, particularly dolutegravir and bictegravir, and may have metabolic implications, especially in women and non-white patients.

Avoid co-administration with antacids or supplements containing polyvalent cations (Ca, Mg, Fe), as they reduce INSTI absorption. 

Timing of administration should be adjusted accordingly.

Use caution during pregnancy and breastfeeding; raltegravir is considered safer in these populations compared to others.

                 Monogragh