What to Know About Integrase Inhibitors

Powerful Antiretrovral Drugs Preferred in First-Line Therapy

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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.

Unrecognizable pharmacist discusses medication with patient
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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):

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

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.

Cabenuva involves a once-monthly dose of cabotegravir and another of a 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.

Before Taking

If you are 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 experienced 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.

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.

Dosage

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

Drug Typical Adult Dosage Dietary Notes
Biktarvy One tablet 1x/daily Taken with or without food
Cabenuva One 400mg cabotegravir injection and one 600mg rilpivirine injection 1x/month Not applicable
Dovato One tablet 1x/day Taken with or without food
Genvoya One tablet 1x/day Taken with food
Isentress One 400mg tablet 2x/day Taken with or without food
Isentress HD One 600mg tablet 2x/day Taken with or without food
Juluca One tablet 1x/day Taken with food
Stribild One tablet 1x/day Taken with food
Tivicay One tablet 1x/day Taken with or without food
Vocabria One tablet taken with one rilpivirine tablet 1x/day Taken with food

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:

Drug Possible Side Effect
Bictegravir Diarrhea
Nausea
Headache 
Weight gain
Cabotegravir Injection site reactions
Fatigue
Fever 
Headache 
Nause
Dolutegravir Insomnia 
Headache 
Weight gain
Liver toxicity
  -Fatigue
  -Nausea
  -Vomiting
  - Jaundice
  -Dark urine
  -Chalky stools
Weight gain
Depression
Elvitegravir Nausea
Diarrhea 
Depression 
Raltegravir Nausea
Diarrhea
Fever
Weight gain
Insomnia
Depression
Rhabdomyolysis
  -Weakness
  -Muscle pain
  -Muscle stiffness
  -Lightheadness
  -Decreased urine output
 

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

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.)

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).

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 other medications as well, leading to adverse events.

Drug INSTIs affected Action
Aluminum and magnesium antacids Bictegravir, dolutegravir, elvitegravir, raltegravir Separate doses by 2 to 6 hours. Avoid with raltegravir.
Antidepressants, antipsychotics, and anxiolytics Elvitegravir Many require a dose adjustment of the accompanying drug.
Antiplatelet drugs like Brinlinta (t icagrelor),  Plavix (clopidogrel), and Zontivity (vorapaxar) Elvitegravir Contraindicated for use. 
Dilantin (phenytoin) and Luminal (phenobarbitol) Bictegravir, dolutegravir, elvitegravir, raltegravir Do not coadminister. Contraindicated with elvitegravir.
Erectile dysfunction drugs Elvitegravir Typically requires a lower dose of the accompanying drug.
Glucophage (metformin) Bictegravir, dolutegravir Monitor for adverse events.
Lipid-modifying drugs Elvitegravir May require a dose adjustment. Contraindicate for use with Altoprev (lovastatin) and Juxtapid (lomitapide). 
St. John's wort Bictegravir, dolutegravir, elvitegravir Do not coadminister with bictegravir and dolutegravir. Contraindicated with elvitegravir.
Tegretol (carbamepazine) Bictegravir, elvitegravir, raltegravir Contraindicated for use
Tikosyn (dofetilide) Bictegravir, dolutegravir, elvitegravir Do not coadminister with elvitegravir. Contraindicated with bictegravir and dolutegravir.
Tuberculosis drugs like rifampin and rifabutin Bictegravir, cabotegravir, elvitegravir Contraindicated for use with bictegravir and elvitegravir. May also require a change of treatment with cabotegravir.

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

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Article Sources
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  6. 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 patientOpen Forum Infect Dis. 2018 Nov 8; 5:ofy294. doi:10.1093/ofid/ofy294

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  8. 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

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