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.
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.
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.
Common and severe side effects vary by the INSTI type:
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.
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.
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