Efavirenz

  • Abbreviation: EFV
    Antiretroviral Subclass:
    Nonnucleoside reverse transcriptase inhibitors

Background

  • U.S. Manufacturer:
    Bristol Myers Squibb

    Approval

    Efavirenz was approved by the FDA in 1998 for use in combination with other antiretrovirals in adults and children with HIV infection. Approval was based on studies showing that initial therapy consisting of efavirenz plus 2 nucleoside analogues or a protease inhibitor, was at least as effective in achieving viral load suppression as were regimens consisting of a protease inhibitor and 2 nucleoside analogues. In one early trial, subjects who received efavirenz + lamivudine + zidovudine were more likely to achieve HIV RNA <50 copies/mL at 48 weeks than recipients of indinavir + lamivudine + zidovudine (by intention-to-treat [ITT] analysis, 64% vs 43%, respectively; p < .05).(1)

    Generic Approval

    The FDA has approved generic versions of efavirenz for use in the United States and has granted "tentative approval" status for purchase and use as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries.

Formulations and Dosing

  • Efavirenz is available in capsule and tablet formulations. For pediatric patients and adults who cannot swallow pills, the contents of efavirenz capsules may be sprinkled on a small amount of food (1-2 teaspoons) or infant formula. Efavirenz also is available in single-tablet combinations with emtricitabine and tenofovir DF (Atripla) and with lamivudine and tenofovir DF (Symfi, Symfi Lo).

    • Efavirenz should be taken on an empty stomach, at bedtime.
    • Efavirenz interacts with a number of antiretroviral medications; see Database of Antiretroviral Drug Interactions for information on recommended dosing adjustments for the interaction of efavirenz with other antiretrovirals.
    • No dosage adjustment is necessary in renal insufficiency.
    • Efavirenz is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C).
    • Please consult product labeling for detailed dosing information.

    Adult Dosing

    Dosage Formulation Notes
    600 mg QD Capsules  

    Key to abbreviations: QD = once daily.

    Efavirenz is potentially teratogenic. If appropriate alternatives exist, it should not be used in pregnant women during the first trimester and should be avoided in women who may become pregnant while taking it.

    Pediatric Dosing

    Age Dosage Formulation Weight
    <3 months Not approved Capsules <3.5 kg
    ≥3 months 100 mg QD Capsules ≥3.5 kg
    ≥3 months 150 mg QD Capsules 5 kg to <7.5 kg
    ≥3 months 200 mg QD Capsules 7.5 kg to <15 kg
    ≥3 months 250 mg QD Capsules 15 kg to <20 kg
    ≥3 months 300 mg QD Capsules 20 kg to <25 kg
    ≥3 months 350 mg QD Capsules 25 kg to <32.5 kg
    ≥3 months 32.5 kg to <40 kg Capsules 400 mg QD
    ≥3 months Adult dosage Capsules ≥40 kg

    Key to abbreviations: QD = once daily.

    Efavirenz is not FDA approved for children <3 months of age or <3.5 kg in weight.

    Formulations

    oval orange tablet
    600 mg
    Image
    oval orange tablet
    yellow capsule
    200 mg
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    yellow capsule
    yellow and white capsule
    50 mg
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    yellow and white capsule

Coformulations

Clinical Use

  • Initial vs Subsequent Therapy

    Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate the combination of efavirenz with tenofovir DF/emtricitabine or tenofovir alafenamide/emtricitabine as "recommended initial regimens in certain clinical situations."

    Numerous studies demonstrate the effectiveness of efavirenz in initial therapy.

    Efavirenz in combination with nucleoside analogue backbones

    Efavirenz given in combination with nucleoside backbones consisting of emtricitabine or lamivudine plus abacavir, didanosine, stavudine, tenofovir, or zidovudine has resulted in high rates of virologic suppression.(2),(3),(4),(5),(6),(7),(8),(9) For example, a randomized study that included a comparison of abacavir + lamivudine + efavirenz with tenofovir + emtricitabine + efavirenz found that, among patients whose pretreatment HIV RNA levels were <100,000 copies/mL, rates of viral suppression to <200 copies/mL were high in both of these treatment groups at 96 weeks (87.4% and 89.2%, respectively), and CD4 increases were roughly 30 points higher in the abacavir + lamivudine group at 48 and 96 weeks).(9) However, among those whose pretreatment HIV RNA was =100,000 at baseline, early virologic failure was seen in a small but statistically significantly greater number of those in the abacavir + lamivudine group.(10)

    An earlier 48-week comparison of tenofovir + emtricitabine with zidovudine + lamivudine, each in combination with efavirenz, found higher rates of virologic suppression in the tenofovir + emtricitabine + efavirenz group (HIV RNA <50 copies/mL in 80% vs 70%; p = .02), as well as greater increases in CD4 cell counts and lower rates of treatment-limiting adverse effects.(6) A comparison of tenofovir + lamivudine + efavirenz with stavudine + lamivudine + efavirenz in antiretroviral-naive patients found the 2 treatments achieved viral loads <50 copies/mL in 81% of each treatment group at week 48 (ITT analysis).(3) However, the combination of tenofovir + didanosine + efavirenz has been shown in 2 small studies to result in high rates of early virologic failure in treatment-naive individuals with high HIV RNA and low CD4 levels at baseline.(11),(12) This combination should be avoided if possible.

    Efavirenz compared with other ARV agents

    In previously untreated patients, combinations that include efavirenz compare favorably with regimens that include either other nonnucleoside reverse transcriptase inhibitors or components from other antiretroviral classes.

    Two parallel randomized, placebo-controlled Phase III studies in antiretroviral-naive adults compared efavirenz with rilpivirine, each in combination with 2 NRTIs (predominantly tenofovir + emtricitabine). By ITT analysis of pooled data from the 2 studies, 82% of efavirenz recipients and 84% of rilpivirine recipients had HIV RNA levels of <50 copies/mL at 48 weeks; the difference was not statistically significant. In patients with HIV RNA >100,000 copies/mL, the efavirenz regimen resulted in higher rates of virologic suppression. The mean increase in CD4 count was 176 cells/µL in the efavirenz group (compared with 192 cells/µL in the rilpivirine group).(13) A randomized trial comparing efavirenz with nevirapine, each given with lamivudine + stavudine in initial therapy, found no significant difference between treatment arms in rates of virologic suppression or in changes in CD4 cell count at 48 weeks.(14)

    In a randomized comparison of efavirenz with ritonavir-boosted atazanavir, each given in combination with either tenofovir + emtricitabine or abacavir + lamivudine, rates of HIV RNA suppression to <50 copies/mL were somewhat higher at 48 weeks in the efavirenz groups (87-90%) than in the atazanavir/ritonavir groups (78-84%).(9) An earlier randomized controlled study of efavirenz vs atazanavir (without ritonavir), each given in combination with lamivudine + zidovudine in initial therapy, showed comparable rates of viral suppression to <50 copies/mL (37% vs 32%) and CD4 increase (approximately 170 cells/µL) at 48 weeks in ITT analysis.(15) In a randomized trial comparing efavirenz and lopinavir/ritonavir, each given with 2 nucleoside analogues, treatment-naive subjects who received efavirenz had higher rates of virologic suppression to <50 copies/mL at 48 weeks (89% for efavirenz recipients and 77% for lopinavir/ritonavir recipients; p = .003), though lower increases in CD4 counts (241 and 285 cells/µL, respectively; p = .01).(16)

    A randomized double-blind comparison of efavirenz and raltegravir in initial therapy, each in combination with tenofovir + emtricitabine, found high rates of virologic suppression to <50 copies/mL at 48 weeks: 82% in the efavirenz group and 86% in the raltegravir arm; the difference was not statistically significant. CD4 increases were 163 cells/µL and 189 cells/µL, respectively.(17) A randomized placebo-controlled comparison of efavirenz + tenofovir + emtricitabine and the fixed-dose coformulation of elvitegravir + cobicistat + tenofovir + emtricitabine found HIV RNA suppression to <50 copies/mL in 84% of efavirenz recipients and 88% of elvitegravir + cobicistat recipients at 48 weeks; the difference was not statistically significant.(18) The mean increase in CD4 count was 206 cells/µL in the efavirenz group and 239 cells/µL in the elvitegravir group.

    Data on the effectiveness of efavirenz in treatment-experienced patients are limited. Subsequent regimens using NNRTIs appear most effective in individuals who have not previously experienced virologic failure while using drugs of this class. In patients with nucleoside analogue experience, combinations containing nelfinavir + efavirenz were more effective at suppressing viral load than regimens containing nelfinavir without efavirenz.(19) In patients with virologic relapse on indinavir-containing regimens, regimens containing nelfinavir + efavirenz + adefovir were effective in the short term, especially if the viral load was <15,000 copies/mL at the time of switching.(20)

    A number of studies (for example (21),(22) have found that switching from a protease inhibitor to efavirenz in the setting of a fully suppressive regimen (with undetectable viral load at the time of switching) does not increase the risk of virologic failure. However, this risk may be increased in antiretroviral-experienced individuals, specifically in those whose HIV is resistant to any component of the regimen.(23)

    Because resistance mutations emerge rapidly when NNRTIs are used in a nonsuppressive combination, efavirenz should be used only as part of a regimen that includes 3 active agents.

    Adverse Effects

    The most common symptomatic adverse effects of efavirenz are neuropsychiatric symptoms such as vivid dreams, sleep alterations, dizziness, and a sense of altered mental state, described as "spacey," "high," or "confused." These usually resolve within the first month of treatment but may persist and may cause discontinuation of treatment. Severe depression, suicidality, or delusions have been infrequently reported. Rash also is common, but is seldom serious and usually resolves after 2-3 weeks without discontinuation of therapy. In some cases, efavirenz-associated rash may be severe and life threatening.

    Efavirenz is teratogenic in nonhuman primates; efavirenz should be avoided in the early weeks of pregnancy, if possible, and should be avoided in women who may become pregnant while taking it (see Special Considerations, below).

    Laboratory abnormalities include elevations in cholesterol and triglycerides.

    Interactions with Other Drugs

    Efavirenz interacts with the cytochrome P450 3A (CYP3A) enzyme system, affecting the hepatic metabolism of many coadministered drugs, including many antiretrovirals. For example, efavirenz accelerates the metabolism of protease inhibitors and the CCR5 antagonist maraviroc, and of many other drugs including rifabutin, itraconazole, some HMG coenzyme A reductase inhibitors (statins), some hormonal contraceptives, methadone, and the hepatitis C protease inhibitors telaprevir and boceprevir; this may lead to subtherapeutic levels of the coadministered drug. Through competition for CYP3A4, efavirenz may inhibit metabolism of a variety of other medications, including bepridil, cisapride, pimozide, ergot derivatives, and some benzodiazepines; this may lead to serious adverse events. Drugs that induce the CYP3A system, such as rifampin, may decrease levels of efavirenz. Efavirenz and voriconazole have a 2-way interaction such that efavirenz levels are increased and voriconazole levels are decreased; if used together, dosages of both drugs must be adjusted. Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

    Resistance

    Resistance to efavirenz is associated with the selection of 1 or more of several resistance mutations.

    Because virus resistant to all available NNRTIs is rapidly selected during failure of an NNRTI-containing regimen, it is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with efavirenz is initiated.

    Implications of efavirenz resistance for treatment with other antiretrovirals

    Resistance mutations selected by efavirenz may be associated with resistance to other NNRTIs. The K103N mutation, which is most commonly selected by efavirenz, confers resistance to nevirapine and delavirdine but as a single mutation does not significantly diminish the efficacy of etravirine. This mutation does not appear to affect the activity of rilpivirine in vitro, but clinical studies that evaluate the response to rilpivirine in the setting of efavirenz resistance are not available.(24) The presence of additional mutations or single mutations other than K103N may cause cross-resistance to rilpivirine and etravirine.

    Implications of resistance to other antiretrovirals for efavirenz treatment

    Resistance to nevirapine, rilpivirine, or delavirdine usually is associated with resistance to efavirenz. NNRTI-associated resistance mutations that arise during treatment with etravirine would be expected to confer resistance to efavirenz, but their effect has not been evaluated in clinical studies.

    Special Uses

    Efavirenz is teratogenic in nonhuman primates, and cases of neural tube defect have been reported in human babies with first-trimester exposure to efavirenz. Efavirenz should be avoided for women who are planning pregnancy or who are at risk of pregnancy and are not using effective contraception, if suitable alternatives exist. Women should be tested for pregnancy, as appropriate, before treatment with efavirenz, and should be counseled about the possible adverse effects of efavirenz on a developing fetus. Current guidelines state that, because the greatest risk to the development of the neural tube occurs during the first 5-6 weeks of pregnancy, before pregnancy typically is recognized, efavirenz may be continued in pregnant women who present for antenatal care during the first trimester, if it is part of a virologically suppressive regimen.(25)

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