Nonnucleoside reverse transcriptase inhibitor
| Clinical Use|
| Use in 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 + emtricitabine as an "alternative" regimen option for initial antiretroviral therapy and the combination of efavirenz with abacavir + lamivudine as an "other" regimen.
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.
| Potential 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 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 Considerations|
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)
|| || Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999;341:1865-73.|
|| || Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med, 2003. 349(24):2293-303.|
|| || Gallant JE, Staszewski S, Pozniak AL, et al; 903 Study Group.Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201.|
|| || DeJesus E, Herrera G, Teofilo E, et al; CNA30024 Study Team. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004 Oct 1;39(7):1038-46.|
|| || Saag MS, Cahn P, Raffi F, et al; FTC-301A Study Team. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA. 2004 Jul 14;292(2):180-9.|
|| || Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60. |
|| || Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004 Apr 29;350(18):1850-61. |
|| || Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006 Aug 16;296(7):769-81. |
|| || Daar ES, Tierney C, Fischl MA, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 5 April 2011;154(7):445-56.|
|| || Sax PE, Tierney C, Collier AC, et al; AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230-40.|
|| || Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-7. |
|| || Maitland D, Moyle G, Hand J, et al. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS. 2005 Jul 22;19(11):1183-8.|
|| || Cohen CJ, Molina JM, Cahn P, et al; ECHO Study Group; THRIVE Study Group. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr. 2012 May 1;60(1):33-42.|
|| || van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004 Apr 17;363(9417):1253-63. |
|| || Squires K, Lazzarin A, Gatell JM, et al. Comparison of Once-Daily Atazanavir With Efavirenz, Each in Combination With Fixed-Dose Zidovudine and Lamivudine, As Initial Therapy for Patients Infected With HIV. J Acquir Immune Defic Syndr. 2004 Aug 15;36(5):1011-1019. |
|| ||Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto. Abstract THLB0204. |
|| || Lennox JL, DeJesus E, Lazzarin A, et al; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806.|
|| || Sax PE, DeJesus E, Mills A, et al; GS-US-236-0102 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012 Jun 30;379(9835):2439-48.|
|| || Albrecht MA, Bosch RJ, Hammer SM, et al; AIDS Clinical Trials Group 364 Study Team. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med. 2001 Aug 9;345(6):398-407.|
|| || Hammer SM, Bassett R, Squires KE, et al; ACTG 372B/D Study Team. A randomized trial of nelfinavir and abacavir in combination with efavirenz and adefovir dipivoxil in HIV-1-infected persons with virological failure receiving indinavir. Antivir Ther. 2003 Dec;8(6):507-18.|
|| || Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. In Infect Dis. 2002 Feb 15;34(4):504-10.|
|| ||Rachlis A, Becker S, Gill J, et al. Successful substitution of protease inhibitors with SUSTIVA (efavirenz) in patients with undetectable plasma HIV-1 RNA levels--results of a prospective, randomized, multicenter, open-label study (DMP 266-049). In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 475.|
|| ||Raffi F, Esnault JL, Reliquet V, et al. The Maintavir Study, Substitution of a non-nucleoside reverse transcriptase inhibitor (NNRTI) for a protease inhibitor (PI) in patients with undetectable plasma HIV-1 RNA: 18 months follow-up. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto. Abstract 474.|
|| || Rimsky L, Vingerhoets J, Van Eygen V, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr. 2012 Jan 1;59(1):39-46.|
|| ||Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. July 31, 2012. Available at aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.|
|| || Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol. 2001 Mar;51(3):213-7.|