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 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.

The INSTI drugs elvitegravir and bictegravir are not sold on their own and are only found in fixed-dose combination drugs.

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 has opened the door for the first time to once-monthly or once-every-two-months dosing.

Before Taking

If you are newly diagnosed with HIV, your healthcare provider 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.

Cabenuva involves a once-monthly or once-every-two-months dose of cabotegravir and of another non-nucleoside drug called rilpivirine. Together, they are as effective in maintaining an undetectable viral load as a daily three-drug therapy taken by mouth.

If you are changing treatment or have experienced treatment failure, your healthcare provider 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.

Dosage

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

Although rare, it is possible to experience transmitted resistance to all available INSTIs, a situation reported in a 2018 issue of Open Forum Infectious Diseases.

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 within 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 healthcare provider if you experience any side effects, particularly if they are persistent or worsening.

In rare instances, depression symptoms induced by dolutegravir, elvitegravir, or raltegravir have led to suicidal thoughts, typically in those with underlying psychiatric conditions.

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 overweight or obesity—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.

On their own, INSTIs pose little risk to the kidneys. However, when used with tenofovir DF, the drugs need to be used with caution if the estimated glomerular filtration rate (eGFR) is below 30 milliliters per minute (mL/min).

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

Let your healthcare provider know about all drugs you take before starting an integrase inhibitor, whether they are prescription, over-the-counter, herbal, nutritional, or recreational.

  • U.S. Department of Health and Human Services. FDA-approved HIV medications.

  • DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV.

  • Hatano H, Lampiris H, Fransen S, et al. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2010 Aug;54(4):389-93. doi:10.1097/QAI.0b013e3181c42ea4

  • ViiV Healthcare. Cabenuva.

  • U.S. Food and Drug Administration. FDA approves Cabenuva and Vocabria for the treatment of HIV-1 infection.

  • Fernandez C, van Halsema CL. Evaluating cabotegravir/rilpivirine long-acting, injectable in the treatment of HIV infection: emerging data and therapeutic potential. HIV AIDS (Auckl). 2019;11:179-92. doi:10.2147/HIV.S184642

  • McGee KS, Okeke NL, Hurt CB, McKellar MH. Canary in the coal mine? Transmitted mutations conferring resistance to all integrase strand transfer inhibitors in a treatment-naive patient. Open Forum Infect Dis. 2018 Nov 8; 5:ofy294. doi:10.1093/ofid/ofy294

  • University of California, San Francisco. Adverse effects of antiretroviral drugs. In: HIV InSite.

  • Ursenbach A, Max V, Maurel M. et al. Incidence of diabetes in HIV-infected patients treated with first-line integrase strand transfer inhibitors: A French multicentre retrospective study. J Antimicrob Chemother. 2020 Nov 1;75(11):3344-3348. doi:10.1093/jac/dkaa330

  • DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Drug interactions between integrase inhibitors and other drugs.

  • HIV.gov. Drug database: Cabotegravir (HIV prevention).

By Mark Cichocki, RN

Mark Cichocki, RN, is an HIV/AIDS nurse educator at the University of Michigan Health System for more than 20 years.  

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