Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

Bristol-Myers Squibb / Merck Sharp & Dohme

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)

The FDA has granted generic versions of efavirenz "tentative approval" status for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. For a table of FDA-approved drugs for use under PEPFAR, see HIV InSite's PEPFAR overview.

Efavirenz is available in capsule and tablet formulations. Efavirenz is also available in combination with emtricitabine and tenofovir as a single tablet (Atripla).

Dosing of Efavirenz Adult* 600 mg QD Pediatric** Birth-3 years Unknown Age >3 yrs and wt 10 to <15 kg 200 mg QD 15 to <20 kg 250 mg QD 20 to <25 kg 300 mg QD 25 to <32.5 kg 350 mg QD 32.5 to <40 kg 400 mg QD >=40 kg Adult dose

Key to abbreviations: wt, weight; QD, once daily. * Efavirenz is potentially teratogenic. It is contraindicated in pregnant women and should be avoided in women with pregnancy potential. ** Efavirenz is not FDA approved for children <3 years. However, it has been studied in younger children; usual doses are indicated.

		Efavirenz should be taken on an empty stomach, at bedtime.

		Efavirenz interacts with a number of antiretroviral medications; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for the interaction of efavirenz with other antiretrovirals.

		No dosage adjustment is necessary in renal insufficiency.

		Please consult product labeling for detailed dosing information.

		FDA Pregnancy Category D.

Efavirenz has been found to be effective in many combination regimens for the treatment of HIV infection, both in previously untreated and in treatment-experienced individuals. Efavirenz has been combined successfully with nucleoside backbones consisting of lamivudine or emtricitabine plus abacavir, didanosine, stavudine, tenofovir, or zidovudine to achieve virologic suppression in a high percentage of recipients.(1,2,3,4,5,6,7) (See "Use in Initial vs Subsequent Therapy")

However, the combination of tenofovir + didanosine + efavirenz has been shown in two 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.(8,9) It is not yet known why this regimen resulted in high failure rates; pending further investigation, this combination should be used with caution.

Because resistance mutations emerge rapidly when NNRTIs are used as monotherapy in the setting of established HIV infection, fully suppressive combinations should be used.

Efavirenz interacts with the cytochrome P450 3A (CYP3A) enzyme system, affecting the hepatic metabolism of many coadministered drugs, including antiretrovirals. For example, efavirenz accelerates the metabolism of the protease inhibitors amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, and saquinavir, and of other drugs such as rifabutin, itraconazole, some HMG coenzyme A reductase inhibitors (statins), and methadone. 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 nevirapine and rifampin, tend to 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, doses of both drugs must be adjusted. Information on drug interactions should be consulted, as dose adjustments are frequently required and some combinations are contraindicated.

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate the combination of efavirenz with tenofovir + emtricitabine as a "preferred" regimen for initial antiretroviral therapy and the combination of efavirenz with abacavir + lamivudine as an "alternative" regimen.

Numerous studies demonstrate the effectiveness of efavirenz in initial therapy. 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.(2,3,4,5,6,10) For example, a comparison of lamivudine + tenofovir + efavirenz with lamivudine + stavudine + efavirenz in antiretroviral-naive patients found the 2 treatments achieved similar rates of viral suppression, with 81% in each arm having viral loads <50 copies/mL at week 48 (intention-to-treat [ITT] analysis, with missing values counted as treatment failure).(3) A 48-week comparison of emtricitabine + tenofovir with lamivudine + zidovudine, each in combination with efavirenz in previously untreated patients, found higher rates of virologic suppression in the emtricitabine + tenofovir + 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)

Efavirenz in combination with lamivudine + zidovudine has been shown to be more effective in suppressing HIV RNA than the 3-nucleoside combination of abacavir + lamivudine + zidovudine.(10) Additionally, in the same study, the 3-drug regimen efavirenz + lamivudine + zidovudine achieved similar rates of virologic suppression at 3 years as the 4-drug regimen efavirenz + abacavir + lamivudine + zidovudine (HIV RNA <50 copies/mL in 85% and 88%, respectively; p = .39).(7)

A randomized, controlled study of efavirenz vs atazanavir, 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.(11) In a randomized comparison between 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 cell counts (241 and 285 cells/µL respectively; p = .01).(12) 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.(13)

Data on the effectiveness of efavirenz in subsequent regimens 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 then regimens containing nelfinavir without efavirenz.(14) 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.(15)

A number of studies (for example 16,17) 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.(18)

The choice of protease inhibitor vs NNRTI in initial therapy is controversial. Treatment with an NNRTI usually consists of fewer pills, and may cause fewer chronic side effects, than treatment with a protease inhibitor. NNRTIs are therefore appealing for patients in whom convenience and tolerability are necessary for adherence. However, several resistance mutations are necessary to confer resistance to all protease inhibitors, while only a single mutation (K103N) is required to confer resistance against all available NNRTIs. For this reason, poor adherence may result in more rapid failure of an NNRTI-based regimen, with more severe consequences for future treatment, than may be the case for a protease inhibitor-based regimen. On the other hand, the long half-lives of efavirenz and nevirapine may allow for occasional missed doses without serum levels falling enough to allow viral replication and selection of resistance.

The most common symptomatic side effect of efavirenz is a sense of altered mental state, described as "spacey," "high," or "confused," which usually resolves within the first month of treatment. Severe depression, suicidality, or delusions have been infrequently reported. Rash is also 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.

In patients taking methadone, efavirenz may precipitate symptoms of withdrawal by lowering blood levels of methadone through a pharmacokinetic interaction.(19) Increases in methadone dose should be considered when efavirenz therapy is initiated.

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.

Resistance to efavirenz is associated with the selection of 1 or more of several resistance mutations. The commonly selected efavirenz resistance mutations confer resistance to delavirdine and nevirapine as well.

Implications of efavirenz resistance for treatment with other antiretrovirals

Resistance mutations selected by efavirenz are usually associated with resistance to delavirdine and nevirapine.

Implications of resistance to other antiretrovirals for efavirenz treatment

Resistance to delavirdine and nevirapine is usually associated with resistance to efavirenz.

Efavirenz is potentially teratogenic. It is contraindicated in pregnancy, particularly in the first trimester. It should also be avoided when there is the potential for pregnancy.