What to Know About Integrase Inhibitors

Integrase inhibitors (INSTIs) are a class of antiretroviral drug that 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 cell'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 five individual INSTI drugs and six fixed-dose combination drugs in which an integrase inhibitor is a component.

These are (by order of release date):

• Isentress (raltegravir)
• Tivicay (dolutegravir)
• Triumeq (dolutegravir + abacavir + lamivudine)
• Stribild (elvitegravir + cobicistat + tenofovir + emtricitabine)
• Genvoya (elvitegravir + cobicistat + tenofovir AF + emtricitabine)
• Juluca (dolutegravir + rilpivirine)
• Biktarvy (bictegravir + tenofovir AF + emtricitabine)
• Dovato (dolutegravir + lamivudine)
• Vocabria (cabotegravir oral)
• Cabenuva (cabotegravir + rilpivirine injectable)

Uses

Integrase inhibitors are used along with other classes of antiretroviral drugs to achieve and sustain viral suppression. They are not used on their own. The drugs can be used in newly treated people as well as those who are treatment-experienced.

First-Line Therapy

As a drug class, INSTIs offer simpler dosing schedules, fewer side effects and interactions, and a lower risk of drug resistance. Because of their enhanced tolerability and durability, they are among the frontline agents used in early HIV treatment. 

In the United States, INSTIs have been given "preferred status" for people newly diagnosed with HIV. In fact, all five recommended first-line therapies involve either bictegravir, dolutegravir, or raltegravir as the backbone of combination therapy.

Subsequent Therapies

Because they are highly effective in overcoming drug-resistant HIV, integrase inhibitors can also be used in treatment-experienced people who have either had a treatment failure or need to change treatments because of intolerable side effects. 

But there other ways in which INSTIs have become true game-changers. The introduction of Cabenuva in January 2021 opened the door for the first time to once-monthly dosing.

Before Taking

If newly diagnosed with HIV, your doctor will perform genetic resistance testing to profile your virus. The blood test is able to detect mutations associated with drug-resistant HIV variants. Based on the number and types of variants you have, the lab can predict with a high degree of accuracy which drugs you are most sensitive to.

If you are changing treatment or have experience treatment failure, your doctor may order an additional phenotypic test that directly exposes the virus to different antiretrovirals to see which are best able to neutralize the virus.

These tests are crucial to ensuring that INSTIs are the appropriate treatment choice. Although INSTIs can overcome many drug-resistant mutations, it is still possible for resistance to be transmitted (that is, passed from one person to the next). In such cases, a person may find themselves with a virus that is either partially or fully resistant to one or more INSTIs.

In addition to genetic testing, a hepatitis B test may be performed. Some INSTIs, like Tivicay and bictegravir, can cause the exacerbation of symptoms in people co-infected with hepatitis B. If the test is positive, these drugs would be avoided.

Dosage

Easy dosing is a highlight of integrase inhibitors. Most approved INSTI formulations require once-daily dosing, while Cabenuva is delivered once-monthly.

Side Effects

Integrase inhibitors are generally well tolerated and tend to have few side effects. Most side effects are transient and will resolve on their own with a week or two of starting treatment. INSTIs rarely cause drug hypersensitivity reactions.

Common and severe side effects vary by the INSTI type:

Call your doctor if you experience any side effects, particularly if they are persistent or worsening,

Warnings and Interactions

Integrase inhibitors can affect glucose metabolism, which in some cases can lead to the onset of type 2 diabetes. Studies remain conflicted on this, with some showing a direct association and others suggesting that pre-existing factors—like a high body mass index (BMI)—are the chief culprits.

Even so, blood glucose monitoring may be routinely performed, particularly in those with prediabetes.

INSTIs can also interact with certain drugs. Among the concerns, they can increase the risk of kidney impairment induced by the antiretroviral drug Viread (tenofovir DF) and other combination drugs containing tenofovir DF (like Complera and Atripla). (The routine monitoring of kidney function is recommended for anyone on a tenofovir-based therapy.)

There are several major interactions affecting one or more INSTIs, some of which may require a dose adjustment, drug substitution, or separation of doses.

Of these, elvitegravir has the most interactions overall as it used with a "booster" drug called cobicistat that can inadvertently boost the accompanying drug as well, leading to adverse events.