Continuing Education Activity

The nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine is used in combination with other antiretroviral therapy (ART) in the treatment of HIV-1, HIV-2, and hepatitis B virus (HBV). It is also used in combination therapy for pre-exposure prophylaxis (PrEP) to prevent HIV infection. Emtricitabine is FDA-approved for use in HIV treatment but is not FDA-approved for the treatment of HBV. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of emtricitabine, pertinent for members of the interprofessional team in the treatment of patients with HIV or who require HIV prophylaxis.

Objectives:

• Review the mechanism of action of NRTIs including emtricitabine.
• Identify the regimens for HIV treatment and prevention that use emtricitabine as a component.
• Outline the need for monitoring and followup when prescribing antiretroviral therapy where emtricitabine is involved.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using ART, including with emtricitabine.

Indications

Antiretroviral therapy (ART) has become the mainstay treatment for patients living with human immunodeficiency virus (HIV). The nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine is used in combination with other ART in the treatment of HIV-1, HIV-2, and hepatitis B virus (HBV).[1] Emtricitabine is FDA-approved for use in HIV treatment but is not FDA-approved for the treatment of HBV.[2] One study showed that emtricitabine at 200 mg helped patients achieve lower HBV DNA load and helped patients achieve normal ALT.[3] For pregnant women with concurrent HIV infection, ART should commence as soon as possible.[4] Options for ART available for pregnant women include the NRTI emtricitabine, along with abacavir, lamivudine, and tenofovir.[4] Early administration of ART in pregnancy reduces the risk of transmitting HIV to the infant.[4] Emtricitabine is a category B drug that does not cause teratogenesis or congenital abnormalities.[1] Emtricitabine safely treats patients with concurrent HIV and hepatitis C infection (HCV), as emtricitabine has few interactions with HCV medications.[4]  

The FDA-approved, combined drug, containing emtricitabine and tenofovir is used as pre-exposure prophylaxis (PrEP) to prevent HIV infection.[5][6] Indications for PrEP use include someone who has sex with an HIV-positive individual, having sex with individuals of unknown HIV status and not being in a monogamous relationship, having a past sexually transmitted infection within the prior six months, using condoms inconsistently in the past, and exchanging sex for money or other goods.[7] PrEP is also indicated for patients using intravenous drugs or entering into a drug rehabilitation program within the last six months.[7] The PROUD study tested the effectiveness of PrEP in HIV-negative men in clinics across England in 2013.[8] The PROUD study reduced the incidence of HIV by 86% in the PrEP group in a patient population where the rate of HIV was seven times greater than the population of men who have sex with men in the same clinics gathered from 2012.[8]

Another indication for emtricitabine is as post-exposure prophylaxis (PEP) after possible exposure to HIV infection. Potential sources of HIV transmission include receptive anal intercourse, insertive anal intercourse, receptive vaginal intercourse, insertive vaginal intercourse, blood transfusion, needlestick injury, sharing needles among intravenous drug users, and mucous membrane exposure.[9] PEP administration should be within 72 hours of possible exposure, and the recommended duration is 28 days.[9] PEP therapy is similar to HIV therapy and includes the use of two NRTI’s with an additional HIV mediation from a different category. The combination pill containing emtricitabine and tenofovir is a common therapeutic choice as a part of PEP therapy due to fewer side effects.[9]

Mechanism of Action

Emtricitabine, a cytosine analog that works as a nucleoside reverse transcriptase inhibitor (NRTI). The chemical structure is 5-Fluoro-1-[2R,5S)-2-(hydroxymethyl)-[1,3]oxathiolane-5-yl]cytosine (FTC).[3] It has a similar chemical structure to lamivudine.[1] Emtricitabine, like other NRTIs, is administered as a prodrug and needs to enter the host cell to be phosphorylated before imparting its antiviral effects.[10] Emtricitabine becomes phosphorylated into the active triphosphate form, emtricitabine 5’-triphosphate, which incorporates into HIV reverse transcriptase of the viral DNA to prevent future HIV DNA synthesis.[1] Emtricitabine inhibits the formation of a 3’-5’-phosphodiester bond between the drug and the 5’-nucleoside triphosphates of the HIV DNA chain leading to cessation of the growing HIV DNA chain.[10] In general, NRTIs work by blocking HIV from using reverse transcriptase, which will prevent the virus from converting its RNA into DNA. Without reverse transcriptase, HIV will be unable to replicate in the human body. Blocking reverse transcriptase helps to lower the HIV viral load and increase the CD4+ T-cell count.[7] Emtricitabine excretion is via the kidneys.[1]

Administration

Emtricitabine is typically administered orally once a day in combination with other antiretroviral therapy (ART).[11] Begin ART as soon as possible after an accurate diagnosis of HIV infection but within the first 14 days.[4] The World Health Organization recommends initiating ART within seven days after diagnosis to decrease viral load.[4] A three-drug regimen is a typical regimen for the initial treatment of HIV consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase inhibitor.[4] The recommended initial regimens include combinations such as tenofovir, emtricitabine, and bictegravir or tenofovir, emtricitabine, and dolutegravir.[4] In the setting of opportunistic infections, ART should commence within the first two weeks.[4] The finding of malignancy in HIV patients constitutes immediate ART therapy.[4]

Emtricitabine has been studied at doses of 25 mg twice per day, 100 mg once daily, 100 mg twice daily, 200 mg once daily, and 200 mg twice per day.[1] All doses studied led to a reduction in HIV viral load, with higher doses leading to more significant reductions.[1] Emtricitabine, combined with other ART, such as didanosine and efavirenz, led to an even more significant decrease in HIV viral loads and an increased CD4+ T-cell count.[1] Studies estimate that a 95% adherence to ART is needed to achieve undetectable viral loads and prevent drug-resistant HIV from emerging.[12] Proper adherence requires patients to take their HIV regimens every day precisely as prescribed by their physician.

Emtricitabine (200 mg) and tenofovir (300 mg) used as pre-exposure prophylaxis are prescribed as a once-daily oral tablet.[13]

Adverse Effects

The adverse effects of emtricitabine are similar to those of other nucleoside reverse transcriptase inhibitors (NRTIs) and include headache, muscle weakness, arthralgia, fatigue, fever, abdominal pain, nausea, vomiting, diarrhea, depression, anxiety, insomnia, rhinitis, cough, and pharyngitis.[1][11] More specifically, emtricitabine has shown an association with skin discoloration.[1] This dermatologic effect presents as hyperpigmentation of the palms and soles, especially in African American patients.[1] Less commonly, skin discoloration can occur on the tongue, arms, lips, and nail beds.[1] Emtricitabine has not correlated with any serious adverse events.[1]  

Emtricitabine combined with tenofovir used as pre-exposure prophylaxis (PrEP) is safe with short-term use of about 2 to 3 years.[14] The common adverse effects associated with this combination include gastrointestinal symptoms, headache, nausea, and depression.[14] This combination has correlated with a decreased creatine clearance that improves with discontinuation of the drug.[14] PrEP can cause a decline in GFR initially, but this decline becomes more gradual the longer a person takes PrEP. PrEP was not associated with severe renal dysfunction, but a decreased GFR was a common presenting finding in patients over the age of 40.[15] This combination has also correlated with a decrease in bone mineral density that returned to normal levels with discontinuation of the drug.[14] Research has not shown the decline in bone mineral density to lead to increased fracture risk.[14] 

Contraindications

Patients with an allergy to any constituent of emtricitabine should avoid taking this drug. Emtricitabine combined with tenofovir as pre-exposure prophylaxis (PrEP) is contraindicated as monotherapy for patients with a positive HIV status. This monotherapy can lead to HIV drug resistance to antiretroviral therapy (ART). Emtricitabine alone has not demonstrated any significant drug interactions.[1] PrEP therapy is contraindicated in patients who have impaired renal function with a creatinine clearance of 60 mL/min.[7] PrEP treatment is also contraindicated in combination with high-dose NSAIDs, acyclovir, valacyclovir, cidofovir, and aminoglycosides.[7]  

Toxicity

Emtricitabine, along with the other drugs in the nucleoside reverse transcriptase inhibitor (NRTI) category, interacts with mitochondrial DNA polymerase, causing myopathy and neuropathy. This toxic interaction also has associations with hepatic steatosis and lactic acidosis. Emtricitabine has not shown any adverse effects on the mitochondrial function of developing fetuses and is not known to be teratogenic. There has been no evidence of emtricitabine affecting the fertility rates of women taking the drug.[1]  

Enhancing Healthcare Team Outcomes

HIV prevention and treatment are the responsibility of an integrated, interprofessional health team comprised of primary care physicians, physician assistants, nurse practitioners, specialty care physicians, nurses, office staff, pharmacists, and laboratory technicians. HIV prevention begins with health education on safer sex practices from the patient’s primary care physician. The primary care providers need to be non-judgmental and well-versed in taking a detailed sexual history using open-ended questions, as well as asking all aspects of the social history, including alcohol and drug use.[16] Every time a patient comes to the primary care clinic, a risk evaluation of contracting HIV is necessary.[4] [Level 5] In addition to HIV testing discussions in the primary care setting, emergency departments and OB/GYN physicians should be offering routine testing.[4] [Level 3]

For high-risk individuals, the benefits of protection from daily pre-exposure prophylaxis (PrEP) can be discussed with patients. The daily PrEP recommended is a combination once-daily pill with emtricitabine and tenofovir. The patient should receive proper education from the primary providers, nurses, and pharmacists before prescribing and using PrEP. These guidelines include using PrEP consistently for one week before sexual activity to allow for adequate drug levels to build in rectal, penile, and vaginal tissue. Patients should also receive reminders to continue PrEP for one week after the last sexual encounter if wanting to discontinue this medication.[4] [Level 5] Nursing should repeat these educational points before the patient leaves to increase understanding of PrEP use. Before prescribing PrEP, HIV testing should take place for all patients, using an antigen-antibody assay to confirm the seronegative status.[4] [Level 3] Other recommendations before prescribing PrEP include measuring serum creatine, GFR, and HBsAg. Patients should be seen at one month after starting PrEP to assess for side effects and adherence and every three months to perform repeat HIV testing. Additional antiretroviral therapy (ART) should be initiated if there is a diagnosis of HIV while a patient is on PrEP.[4] [Level 5] Hepatitis C virus (HCV) should be tested annually for those on PrEP therapy. Creatinine measurements should be performed every six months and more often for patients concurrently taking hypertension or diabetes medications, those over the age of 50, and those with a GFR less than 90 mL/min.[4] [Level 3] Every subsequent visit while on PrEP should be used to discuss safe sex measures such as condom use and daily adherence to the medication. Any patient with hepatitis B virus (HBV) who is taking PrEP that includes emtricitabine requires close monitoring if discontinuing the medication due to liver damage from reactivation of the HBV.[16] 

Every patient should receive an HIV test at least once in their lives, with specific populations needing more frequent testing. Men having sex with men, transgender women, and intravenous drug users should have HIV testing at least one time per year and as frequently as every three months. Patients who present with sexually transmitted infections and HCV should be screened for HIV more often.[4] [Level 5[4] When testing for HIV, the health care team needs to explain how HIV testing methodology, how long until the results return, and that they must report positive results to the state health department.[17] HIV testing recommendations include combination antibody-antigen assay or combination antibody assay with nucleic acid testing.[4] [Level 3] Further testing of the HIV viral load is the recommendation before prescribing ART.[4] [Level 1] Patients found to be HIV-positive need a referral to infectious disease or an HIV specialist. Further testing of HIV viral load and HIV genotype should take place before prescribing ART. HIV genotype testing before medical therapy shows which medications the specific strain of HIV may have resistance.[4] [Level 5] The comorbidities of these patients need to be documented well in the electronic health record, especially if the patient has concurrent HBV. Liver enzymes and HBV DNA viral load become elevated when a patient stops taking emtricitabine abruptly.[1] Primary care and infectious disease providers need to monitor the patient for signs of liver damage for weeks after discontinuing emtricitabine.[1] It is also essential for a health care provider to address the mental health of a newly diagnosed HIV patient and those living with HIV, with referral to psychiatry or counseling a possibility. The health care team must keep track of when their patients receive their medications, and when they come to their appointments.[4] [Level 3][4] The entire office, including the front desk administration, can assist with reminding patients of appointments and follow-ups.[4] [Level 1] Every visit presents an opportunity to discuss adherence to ART, screen for an understanding of medications, and reiterate the importance of safe sex practices and honesty of diagnosis for those with HIV. Screening the social factors of this patient population is vital to guarantee these patients can afford their medications, understand how to take their medications, have support from family and friends, and have access to proper transportation to and from the physician’s office. It may be necessary to bring in a social worker to help further address the social needs of this patient population.

Finally, it is the responsibility of health care providers to advertise the short-term use of drugs like emtricitabine in combination with other HIV medications as post-exposure prophylaxis (PEP).[9] Patients should be made aware of HIV exposure risks and when and how to seek therapy. Protocols should be in place by physician’s offices and hospitals for possible HIV exposure. This protocol includes determining the HIV status of the patient who is requesting PEP therapy and the HIV status of the subject with whom the patient was in contact with if possible.[9] One should also assess the timing and frequency of HIV exposure, the risk of exposure, and the possibility for other sexually transmitted infections.[9] Finally, it is essential to educate the patient on safe sex and how to reduce occupational exposures and follow up to determine adherence to the therapy and side effects with the treatment.[9] Patients requesting PEP should be evaluated by a health care worker that can stratify risk factors and determine whether the patient’s exposure needs ART. PEP therapy should be readily available to all health care workers, along with laboratory testing in the case of occupational exposure. Testing for occupation therapy should be promoted and simplified, so health care workers can feel comfortable coming forward to protect their health.