What to Know About Odefsey (Emtricitabine, Tenofovir AF, Rilpivirine)

Next-generation three-in-one drug offers fewer side effects

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Odefsey is a single-pill, fixed-dose combination drug used in the treatment of HIV. Available in tablet form, it can be used in adults and some children. It is comprised of three different antiretroviral agents:

  • Emtricitabine, commonly called FTC, a nucleoside reverse transcriptase inhibitor (NRTI)
  • Rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI)
  • Tenofovir alafenamide (TAF), another NRTI

Odefsey is used on its own and does not require any additional drugs to achieve and sustain viral suppression.

Person holding a pill between their thumb and forefinger against a blue background

Gilead Sciences

Odefsey works by inhibiting different stages of HIV's replication cycle. Both FTC and TAF block an enzyme called reverse transcriptase that HIV uses to convert its viral RNA into DNA to "hijack" the cell's genetic machinery. Rilpivirine works similarly but rather than blocking the formation of double-stranded DNA, it binds to the enzyme itself to block its activity.

Odefsey is the second combination antiretroviral to use TAF, an "improved" form of tenofovir disoproxil fumarate (TDF) found in the drugs Truvada (FTC + TDF) and Atripla (efavirenz + FTC + TDF). As such, it can be considered an improvement on TDF-based Complera (FTC + rilpivirine + TDF). 

TAF differs from TDF in that it requires a far smaller dose to achieve the same effects. As a prodrug—meaning an inactive compound that is metabolized in the body to produce a drug—TAF causes less drug accumulation in the bloodstream, lowering the risk of kidney toxicity seen with TDF.


Odefsey was approved by the Food and Drug Administration (FDA) in March 2016 for use in adults and children weighing at least 35 kilograms (77 pounds). It is indicated for use in newly treated people who have a viral load of 100,000 or less.

Odefsey can also be used to replace a current therapy (such as Complera) if the person has had an undetectable viral load for at least six months, has no history of treatment failure, and has no resistance to any of the antiretrovirals used in Odefsey.

There are no off-label uses for Odefsey and no generic forms of the drug.

Before Taking

When diagnosed with HIV, your healthcare provider will order a genetic resistance test to determine if you have any drug-resistant variants in your "viral pool." Based on the results of the test, also known as genotyping, your healthcare provider can determine which antiretrovirals you are sensitive to and which you are not.

Because drug resistance can be transmitted—that is, passed from one person to the next—genetic resistance testing is considered imperative for selecting the drugs with the greatest overall sensitivity and durability.

If you are being switched to Odefsey, your healthcare provider may also order a phenotypic test in which your virus is individually exposed to antiretroviral drugs to determine which ones you are most sensitive to.

Precautions and Contraindications

Odefsey is contraindicated for use in people on medications that can reduce the concentration of rilpivirine in the bloodstream (see "Warnings and Contraindications" below). It is also never used in people who have had a severe hypersensitive reaction to FTC, rilpivirine, or tenofovir in either form.

Rilpivirine can also prolong the QT interval on an electrocardiogram and potentially lead to a heart rhythm disorder called torsades de pointes. Your healthcare provider will need to determine if you take any drugs that cause QT prolongation and, if so, decide whether Odefsey is a reasonable option for you.

Before starting Odefsey, advise your healthcare provider of any drugs you take, whether they are prescription, over-the-counter, herbal, nutritional, or recreational.

Because the various antiretroviral agents in Odefsey are eliminated via the kidneys or liver, Odefsey should be used with caution in people with pre-existing kidney or liver dysfunction as it can lead to toxicity. If used in these circumstances, the routine monitoring of kidney function and/or liver function is essential.

Other Fixed-Dose Combination Antiretrovirals

In addition to Odefsey, there are 12 other combination drugs that can be taken on their own with one pill daily:

  • Atripla (efavirenz + FTC + TDF)
  • Biktarvy (bictegravir + FTC + TAF)
  • Complera (FTC + rilpivirine + TDF)
  • Delstrigo (doravirine + lamivudine + TDF)
  • Dovato (dolutegravir + lamivudine)
  • Genvoya (cobicistat + elvitegravir + FTC + TAF)
  • Juluca (dolutegravir + rilpivirine)
  • Stribild (cobicistat + elvitegravir + FTC + TDF)
  • Symfi (efavirenz + lamivudine + TDF)
  • Symfi Lo (efavirenz + lamivudine + TDF)
  • Symtuza (cobicistat + darunavir + FTC + TAF)
  • Triumeq (abacavir + dolutegravir + lamivudine)

In January 2021, the FDA approved a combination injectable antiretroviral therapy called Cabenuva (cabotegravir and rilpivirine), which can be given monthly or every two months.


Odefsey is available as a gray, oblong, film-coated tablet, comprised of 200 milligrams (mg) of FTC, 25 mg of rilpivirine, and 25 mg of TAF. It is embossed with "GSI" on one side and "255" on the other.

Odefsey is taken by mouth once daily with food.

Because Odefsey is a fixed-dose drug, the dose cannot be modified.

How to Take and Store

Odefsey must be taken with solid food in order for rilpivirine to be properly absorbed. Protein drinks or nutritional drinks will not do. If not taken with food as prescribed, the absorption of rilpivirine may be reduced by as much as 40%.

Do not split, crush, or chew the tablet, all of which can affect absorption.

If you miss a dose of Odefsey, take it as soon as you remember. If it is near the time of your next dose, skip the original dose and continue as normal. Do not double up doses.

Odefsey can be stored safely at room temperature, ideally in its original light-resistant container in a cool, dry cabinet or drawer. Always check the expiration date, discarding any drugs that have expired.

Side Effects

Odefsey may cause side effects in some people. Most are generally transient and will resolve over the course of days or weeks as your body adapts to treatment. Many people experience no side effects at all.


The most common side effects experienced in as many as 2% of users include:

  • Headache
  • Nausea
  • Flatulence
  • Diarrhea
  • Insomnia
  • Unusual dreams


In rare instances, Odefsey can cause severe side effects. These often involve people with pre-existing conditions (or take contraindicated drugs) who have not been appropriately screened.

Some of the most serious complications associated with Odefsey include:

  • Acute exacerbations of hepatitis B: Symptoms include fatigue, nausea, jaundice (yellowing of the eyes), abdominal pain, loss of appetite, and dark urine.
  • Liver toxicity: Symptoms are similar to acute hepatitis B but may also involve rash and fever.
  • New or worsening kidney impairment: Symptoms may include decreased urine output, fatigue, shortness of breath, nausea, and tissue swelling due to fluid retention.
  • Lactic acidosis: The abnormal buildup of lactic acid in the bloodstream can become severe and even life-threatening if left untreated.
  • Severe skin reactions: Rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in users, manifesting with severe rash, blisters, fever, facial swelling, and hepatitis.
  • Severe depression: Major depressive episodes, including suicidal thoughts, have been reported in some users of rilpivirine. This is mostly seen in people under 18.
  • Torsades de pointes (TDP): Generally seen in people who take drugs that prolong the QT interval, TDP symptoms include heart palpitations, dizziness, nausea, cold sweats, chest pain, shortness of breath, and rapid pulse.

Warning and Interactions

Odefsey carries a black box warning advising consumers about the risk of a potentially severe flare-up of hepatitis symptoms in people co-infected with hepatitis B if Odefsey is stopped. If Odefsey is discontinued, liver function should be monitored and anti-hepatitis B treatment started should a flare-up occur. (People prescribed Odefsey will also be given a hepatitis B test prior to the start of treatment to check if they have the disease.)

Odefsey may be continued in women who become pregnant with an undetectable viral load. However, because rilpivirine absorption may be reduced during pregnancy, women who do not have complete viral suppression may need to be changed to a more active drug combination.

Breastfeeding is not recommended for any mother with HIV, irrespective of treatment, to better avoid the risk of mother-to-child transmission.

Drug Interactions

Odefsey can interact with certain drugs, which may affect drug concentrations or trigger adverse symptoms, such as torsades de points.

Tell your healthcare provider if you take any of the following drugs in either their brand name or generic forms:

In some cases, an interaction may require a dose reduction, drug substitution, or the separation of doses by several hours. In others, no change may be needed.

9 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.
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  2. Gilead Sciences. Package insert - Odefsey.

  3. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Laboratory testing.

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

  5. Food and Drug Administration. Cabenuva label.

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  7. Mehta R, Piscitelli J, Wolstenholme A, et al. The effect of moderate- and high-fat meals on the bioavailability of dolutegravir/rilpivirine fixed-dose combination tablet. eClin Pharmacol. 2020;12:49-52. doi:10.2147/CPAA.S250751

  8. Osiyemi O, Yasin S, Zorrilla C, et al. Pharmacokinetics, antiviral activity, and safety of rilpivirine in pregnant women with HIV-1 Infection: Results of a phase 3b, multicenter, open-label study. Infect Dis Ther. 2018 Mar;7(1):147-59. doi:10.1007/s40121-017-0184-8

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By James Myhre & Dennis Sifris, MD
Dennis Sifris, MD, is an HIV specialist and Medical Director of LifeSense Disease Management. James Myhre is an American journalist and HIV educator.