HIV/AIDS Treatment What to Know About Integrase Inhibitors Powerful Antiretrovral Drugs Preferred in First-Line Therapy By Mark Cichocki, RN twitter linkedin Mark Cichocki, RN, is an HIV/AIDS nurse educator at the University of Michigan Health System for more than 20 years. Learn about our editorial process Mark Cichocki, RN Medically reviewed by Medically reviewed by Latesha Elopre, MD, MSPH on May 24, 2020 linkedin Latesha Elopre, MD, is a board-certified internist specializing in HIV. She is an assistant professor of infectious diseases at the University of Alabama at Birmingham. Learn about our Medical Review Board Latesha Elopre, MD, MSPH Updated on February 21, 2021 Print Table of Contents View All Table of Contents Uses Before Taking Dosage Side Effects Warnings & Interactions 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. SDI Productions / Getty Images 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) The INSTI drugs elvitegravir and bictegravir are not sold on their own and are only found in fixed-dose combination drugs. Why Are There So Few Generic HIV 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. How Much Do HIV Drugs Cost? 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. 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. 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. What to Do If You Have HIV and Viral Hepatitis 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 rilpivrine 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 50mg tablet 1x/day Taken with or without food Vocabria One 30mg tablet taken with one 25mg rilpivrine tablet 1x/day Taken with food How Much HIV Drug Adherence Is Enough? 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: 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, How to Decipher Routine HIV Blood Tests 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 the accompanying drug 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 Contraindiated 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 Many 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 and all drugs you take before starting an integrase inhibitor, whether they are prescription, over-the-counter, herbal, nutritional, or recreational. 6 Drugs to Avoid If Taking HIV Therapy Was this page helpful? Thanks for your feedback! Get information on prevention, symptoms, and treatment to better ensure a long and healthy life. Sign Up You're in! Thank you, {{form.email}}, for signing up. There was an error. Please try again. What are your concerns? Other Inaccurate Hard to Understand Submit Article Sources Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy. U.S. Department of Health and Human Services. FDA-approved HIV medications. Updated September 28, 2020. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Updated December 18, 2019. 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 U.S. Food and Drug Administration. FDA approves Cabenuva and Vocabria for the treatment of HIV-1 infection. January 27, 2021. 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. Updated June 2018. 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. Updated December 18, 2019. Additional Reading HIV.gov. Drug database: Cabotegravir (HIV prevention). Updated July 13, 2020.