Treating HIV With Integrase Inhibitors

Integrase inhibitors are a class of antiretroviral drug which prevents HIV from inserting its genetic code into the DNA of an infected cell. It does this by blocking an enzyme known as integrase that HIV needs to hijack the host's DNA and start churning out copies of itself.

Isentress (raltegravir) was the first integrase inhibitor approved by the U.S. Food and Drug Administration (FDA) on October 12, 2007. All told, there are currently three approved INSTI drug molecules and five fixed-dose combination drugs in which an integrase inhibitor is a component.

They are (by order of release date):

• Isentress (raltegravir)
• Tivicay (dolutegravir)
• Vitekta (elvitegravir)
• Triumeq (dolutegravir + abacavir + lamivudine)
• Stribild (elvitegravir + cobicistat + tenofovir + emtricitabine)
• Genvoya (elvitegravir + cobicistat + tenofovir AF + emtricitabine)
• Juluca (dolutegravir + rilpivirine)
• Biktarvy (bictegravir + tenofovir AF + emtricitabine)

As a drug class, integrase inhibitors offer simpler dosing schedules, fewer side effects, and a lower risk of drug resistance. Because of this, they are one of the preferred drugs used in early HIV treatment. 

In the United States, integrase inhibitors are classified as one of the preferred, first-line drugs for people newly diagnosed with HIV. In fact, all five recommended first-line therapies include an integrase inhibitor as the backbone of treatment.

How Integrase Inhibitors Work

HIV integrates its genetic material (genome) into the host cell's DNA in a five-step process:

1. The integrase enzyme binds to HIV DNA, the latter of which is created in a process called reverse transcription.
2. The HIV DNA is then prepared for integration in a process called cleaving, which splits the viral genetic strand, leaving open gaps in its structure.
3. The cleaved strand is then inserted into the host cell's nucleus through an opening called the nuclear pore.
4. Once inside the nucleus, the HIV DNA is transferred into the host DNA in is what's called a strand transfer reaction. In this stage, the viral DNA will literally tear the host cell's DNA apart, separating the bonds that hold it together and inserting itself into the chemical gaps in the DNA strand.
5. The process is completed by natural protective response called gap repair, in which the host cell will automatically repair any damage to the DNA, essentially facilitating the takeover of its genetic coding.

By blocking the integrase enzyme, the entire integration process is stopped before it can even start.

Integrase inhibitors block only one stage of the HIV life cycle. Other HIV drugs, known as nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, and CCR5 antagonists, block different stages in the life cycle.

When used in combination, they can effectively suppress HIV activity to undetectable levels.

Side Effects and Considerations

Unlike other classes of HIV drug, integrase inhibitors work directly on the mechanisms of viral activity rather than on the infected cells. As such, they tend to have fewer side effects, primarily diarrhea, nausea, fatigue, headache, and insomnia.

Most of these side effects are transient and usually resolve on their own with a week or two of starting treatment. With that being said, if you experience any side effects, call your doctor immediately and do not stop treatment until your doctor tells you. Stopping and changing treatment prematurely can lead to the development of drug resistance.

With that being said, integrase inhibitors remain longer in the bloodstream than other HIV drugs and have greater "forgiveness" if you occasionally miss a dose. Still, it's important to remain adherent, taking it every day as prescribed with as few missed doses as possible.

Drugs in Development

While the combination drug, Dutrebis (raltegravir + lamivudine), had received approval by the FDA in 2015, the manufacturer has decided not to release it in the U.S. and later withdrew it from the European Union, as well. In the end, the manufacturer decided that it was unnecessary given that raltegravir and lamivudine are already widely distributed as single drug agents.

Another promising candidate, the integrase inhibitor cabotegravir, is undergoing Phase III human trials.