How Do Integrase Strand-Transfer Inhibitors Work in Antiretroviral Therapy for HIV Infection?

Integrase strand-transfer inhibitors (INSTIs) are one of the latest additions to the classes of drugs used in antiretroviral therapy (ART) for human immunodeficiency (HIV) infection. The first integrase strand-transfer inhibitor came into use in 2007, as part of the ART regimen with nucleoside reverse transcriptase inhibitors (NRTIs).

INSTIs are often a part of fixed-dose, single pill, combination drug formulations for ART. INSTIs, as a part of a complete ART regimen, are approved for treatment of children with HIV infection, who are 12 or older and weigh at least 40 kg.

INSTIs are effective as initial therapy in controlling viral growth in treatment-naive HIV patients. INSTIs are also used to reduce the viral load in treatment-experienced patients, who develop resistance to multiple other antiretroviral drug classes.

Antiretroviral therapy is a treatment regimen for HIV infection, using a combination of three or more drugs that prevent viral replication at different stages in its replication cycle. HIV infection has no cure, but ART can effectively control viral growth and keep an HIV infected person healthy and active for many years.

HIV infection is caused by a virus that infects and weakens the human immune system. The virus enters a human immune cell known as T-cell, and uses its cell machinery to replicate itself. 

Without treatment, HIV infection in its later stages can progress to acquired immune deficiency syndrome (AIDS), when the immune system is so severely impaired it is unable to fight even common infections effectively.

HIV is a microscopic scrap of genetic matter that consists of a single strand of RNA encased in a protein capsule. Viruses are incapable of reproducing on their own; they use the machinery of a living host cell to replicate themselves.

There are several stages in the process of HIV’s replication. Once the virus enters through the cell membrane into the T-cell’s cytoplasm (fluid inside the cell), it converts its RNA strand into a double-strand DNA using an enzyme known as reverse transcriptase.

The viral DNA then releases another enzyme known as integrase, which transports the viral DNA strand into the T-cell’s nucleus and inserts it into the T-cell’s DNA. Once integrated with the host DNA, the virus can build the necessary protein chain to create more viral particles.

The integrase strand-transfer inhibitors bind metallic ions at the insertion site in the T-cell DNA, preventing the viral DNA strand transfer by the integrase enzyme. The viral DNA is then degraded and cannot multiply.

The INSTIs have a high barrier to resistance development by HIV, especially the second generation INSTIs. INSTI resistance may still develop gradually with HIV mutations.

INSTIs are relatively safe and better-tolerated than other HIV drugs. Some of the common side effects are:

• Mild to moderate gastrointestinal effects such as
  • Nausea
  • Vomiting
  • Diarrhea
• Headache
• Insomnia

Following are some rarer side effects:

• Muscle damage (myopathy)
• Skeletal muscle breakdown (rhabdomyolysis)
• Malignant tumors
• Kidney damage
• Hypersensitivity reactions
• Depression and suicidal thoughts

Following are the two FDA-approved INSTIs that are currently part of antiretroviral therapy, and some of their common side effects:

Raltegravir (Isentress, Isentress HD)

Available as tablets, for treatment-naïve and patients with well controlled viral load.

Side effects include:

• Nausea
• Diarrhea
• Headache
• Creatine kinase (CK) elevation (sign of muscle damage)
• Myopathy and rhabdomyolysis (rare)
• Hypersensitivity reactions (rare)
• Depression and suicidal thoughts (rare)

Dolutegravir (Tivicay)

Available as tablets, for treatment-naïve patients and treatment-experienced patients with resistance to multiple antiretroviral drug classes.

Side effects include:

• Cholesterol and triglyceride elevation
• CK elevations
• Liver enzyme elevations
• Hyperglycemia (high blood sugar levels)
• Hypersensitivity reactions (rare)
• Depression and suicidal thoughts (rare)

The following are two more INSTIs which are currently available as a part of fixed dose, single pill combinations:

• Elvitegravir
• Bictegravir