Efavirenz

Article Author:
Jessica Yee
Article Editor:
Charles Preuss
Updated:
5/30/2019 12:15:11 AM
PubMed Link:
Efavirenz

Indications

Efavirenz is an FDA-approved medication used for the treatment and prevention of HIV. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Like the majority of other NNRTI agents, its most common use is in combination with other agents with different mechanisms of action in antiretroviral therapy (ART) regimens. Due to its unfavorable side effect profile, it has fallen somewhat out of favor.[1]

  • FDA-labeled indications
    • HIV infection
  • Non-FDA labeled indications
    • HIV infection prophylaxis (occupational exposure, perinatal transmission)

Mechanism of Action

Efavirenz is a non-nucleoside reverse transcriptase inhibitor drug (NNRTI). It binds to a non-catalytic site of the HIV reverse transcription enzyme, thereby inhibiting its activity. This action consequently blocks DNA polymerase activities, including HIV replication. Though therapeutic drug concentration monitoring is not necessary for efavirenz, it is essential to achieve adequate serum concentrations. Low concentrations are associated with virologic failure, while higher concentrations are associated with increased adverse effects such as sleep disorders.[2]

The administration of efavirenz with food has shown to increase the serum concentrations and the incidence of side effects. For this reason, patients should not take efavirenz with food.[3] Peak concentrations are reached by 5 hours following a single oral dose, with steady-state plasma concentrations achieved in 6 to 7 days. The half-life of efavirenz is roughly 45 hours, making once daily dosing suitable. Efavirenz is highly protein bound to human plasma proteins, predominantly albumin. Efavirenz converts to inactive hydroxylated metabolites by the action of the CYP3A4 enzyme.[4] 

It is available in combination with other antiviral medications.[5]

Administration

Efavirenz is available by prescription only, and it is available as an oral capsule and an oral tablet. It is also available as a component of two combination drugs: efavirenz, emtricitabine, and tenofovir disoproxil fumarate, and efavirenz, lamivudine, and tenofovir disoproxil fumarate. The capsules are available as 200 mg and 50 mg, while the tablets are available as 600 mg. The recommended adult dose is 600 mg per day, but there has been data showing that 400 mg per day yields equivalent outcomes with fewer side effects.[6]

The manufacturer recommends no renal dose adjustments. No dose adjustments are necessary for mild hepatic impairment (Child-Pugh class A), but caution is advisable. Efavirenz is not recommended in patients with moderate to severe impairment (Child-Pugh class B or C).

Efavirenz dosing should be on an empty stomach, as increased efavirenz serum concentrations occur when taken with food. Increased serum concentrations can lead to increased adverse effects.[7] 

Adverse Effects

NNRTIs as a drug class are commonly associated with central nervous system (CNS) effects. Among these are impaired concentration, vivid or abnormal dreams, insomnia, suicidal ideation, nausea, and vomiting.[8] Patients who experience these adverse effects are more likely to be non-adherent and discontinue their antiretroviral therapy, leading to virologic failure.[9] These symptoms typically arise in the first few days of treatment and decline within a few weeks of continued treatment.[4]

Like the majority of the NNRTIs, efavirenz correlates with a wide array of drug interactions due to the phase I cytochrome P450 (CYP) enzymes. Efavirenz is a substrate, inducer, and inhibitor of CYP3A4.[10] 

Lipodystrophy is also a class-wide effect of NNRTIs and may occur during treatment with efavirenz.[4]

Contraindications

The use of efavirenz is contraindicated in patients with previously documented hypersensitivity to efavirenz and patients concurrently receiving elbasvir/grazoprevir due to a CYP3A4 interaction. Efavirenz acts as a CYP3A4 inducer, in this case, by decreasing the serum concentrations of grazoprevir.[11] The use of efavirenz is also contraindicated in pregnant women in the first trimester due to reports of neural tube defects. 

Monitoring

As one of the predominant side effects of efavirenz, psychiatric effects require monitoring in all patients. In the event that these symptoms do occur, the prescriber can attempt dose adjustments before changing medications. Due to the potential for hepatotoxicity, serum transaminases also require periodic monitoring.

Toxicity

Toxicity of this drug is generally related to the adverse effects associated with it, which are relative to serum concentrations. Overdose is uncommon and life-threatening sequelae from acute overdose are rare. There is no available antidote for efavirenz overdose.

Enhancing Healthcare Team Outcomes

Treatment with efavirenz can significantly improve the quality of life of patients infected with HIV, but its efficacy heavily relies on patient adherence. The neurologic side effects associated with efavirenz cause some patients to discontinue therapy. It is crucial that an interprofessional team of healthcare providers becomes actively involved with the care of their HIV-positive patients. Key members of the team include pharmacists, physicians, nurses, and social workers. Obstacles to successful ART may include a lack of social support and financial burden of therapy. Healthcare providers play a critical role in providing counseling regarding methods of coping with these side effects and promoting medication adherence. Identifying appropriate opportunities for members of each discipline to provide care and encouragement is crucial to successful ART.[12]

The following are recommendations for healthcare providers to assist in increasing successful outcomes in patients diagnosed with HIV on ART[13]:

  • Monitoring of successful entry into HIV care is recommended for individuals diagnosed with HIV (Level IIA)
    • Entry into care, defined as a visit with an HIV care provider, has demonstrated correlations with improved survival. 
  • Providers should obtain self-reported adherence routinely. (Level IIA)
    • Healthcare providers should ask patients about their adherence at appointments.
  • Pharmacy refill data is recommended for adherence monitoring if medication refills are not automatically sent to patients. (Level IIB)
    • Pharmacy refill data can be used to confirm self-reported adherence.
  • Switching treatment-experienced patients receiving complex or poorly tolerated regimens to simpler once-daily regimens is recommended if regimens have equivalent efficacy. (Level IIIB)
    • A higher pill burden is associated with lower adherence. Discussing with the patient about pill burden can identify an opportunity for improving adherence.
  • Individual one-on-one ART education is recommended (Level IIA)
    • Counseling, skills-building, and education have been shown to increase adherence rates.
  • an interprofessional education and counseling intervention approaches are recommended (Level IIIB)
    • Interprofessional teams can provide education regarding multiple factors that affect adherence.
  • Case management is recommended to minimize the number of adherence barriers in the homeless (Level IIIB)
    • Assistance in acquiring mental health and substance abuse treatment and housing accommodations can significantly improve outcomes.

In summary, efavirenz therapy, as with all ART,  requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


References

[1] Caniglia EC,Phillips A,Porter K,Sabin CA,Winston A,Logan R,Gill J,Vandenhende MA,Barger D,Lodi S,Moreno S,Arribas JR,Pacheco A,Cardoso SW,Chrysos G,Gogos C,Abgrall S,Costagliola D,Meyer L,Seng R,van Sighem A,Reiss P,Muga R,Hoyos SP,Braun D,Hauser C,Barrufet P,Leyes M,Tate J,Justice A,Hernán MA, Commonly Prescribed Antiretroviral Therapy Regimens and Incidence of AIDS-Defining Neurological Conditions. Journal of acquired immune deficiency syndromes (1999). 2018 Jan 1     [PubMed PMID: 28991888]
[2] McDonagh EM,Lau JL,Alvarellos ML,Altman RB,Klein TE, PharmGKB summary: Efavirenz pathway, pharmacokinetics. Pharmacogenetics and genomics. 2015 Jul     [PubMed PMID: 25966836]
[3] Robarge JD,Metzger IF,Lu J,Thong N,Skaar TC,Desta Z,Bies RR, Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition. Antimicrobial agents and chemotherapy. 2017 Jan     [PubMed PMID: 27799204]
[4]     [PubMed PMID: 19767318]
[5] Desta Z,Gammal RS,Gong L,Whirl-Carrillo M,Gaur AH,Sukasem C,Hockings J,Myers A,Swart M,Tyndale R,Masimirembwa C,Iwuchukwu OF,Chirwa S,Lennox J,Gaedigk A,Klein T,Haas DW, Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-containing Antiretroviral Therapy. Clinical pharmacology and therapeutics. 2019 Apr 21;     [PubMed PMID: 31006110]
[6]     [PubMed PMID: 25877963]
[7] Homkham N,Cressey TR,Bouazza N,Ingsrisawang L,Techakunakorn P,Mekmullica J,Borkird T,Puangsombat A,Na-Rajsima S,Treluyer JM,Urien S,Jourdain G, Role of efavirenz plasma concentrations on long-term HIV suppression and immune restoration in HIV-infected children. PloS one. 2019;     [PubMed PMID: 31095608]
[8] Apostolova N,Blas-Garcia A,Galindo MJ,Esplugues JV, Efavirenz: What is known about the cellular mechanisms responsible for its adverse effects. European journal of pharmacology. 2017 Oct 5;     [PubMed PMID: 28690189]
[9]     [PubMed PMID: 26788406]
[10]     [PubMed PMID: 23385314]
[11] Rice DP Jr,Faragon JJ,Banks S,Chirch LM, HIV/HCV Antiviral Drug Interactions in the Era of Direct-acting Antivirals. Journal of clinical and translational hepatology. 2016 Sep 28;     [PubMed PMID: 27777891]
[12] Chendi BH,Okomo Assoumou MC,Jacobs GB,Yekwa EL,Lyonga E,Mesembe M,Eyoh A,Ikomey GM, Rate of viral load change and adherence of HIV adult patients treated with Efavirenz or Nevirapine antiretroviral regimens at 24 and 48 weeks in Yaoundé, Cameroon: a longitudinal cohort study. BMC infectious diseases. 2019 Feb 26;     [PubMed PMID: 30808298]
[13]     [PubMed PMID: 22393036]