Efavirenz (Sustiva)

Efavirenz (Sustiva) is an anti-HIV drug that reduces the amount of virus in the body. Anti-HIV drugs such as efavirenz slow down damage to the immune system and prevent the occurrence of AIDS-defining illnesses.

Efavirenz belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). The enzyme reverse transcriptase converts single-stranded viral RNA into DNA. Drugs in the NNRTI class stop HIV from replicating within cells by binding near reverse transcriptase’s active site and inhibiting polymerase activity.

Efavirenz, formerly known by the codename DMP 266, was developed by Du Pont Pharma. It was approved for HIV treatment in the United States in 1998, and the European licence was granted in May 1999.

Efavirenz is marketed by Bristol-Myers Squibb under the trade name Sustiva in the United States, United Kingdom, Ireland, France, Germany, Italy, and Spain. The trade name Stocrin is used by Merck Sharp & Dohme, who market the drug in other European countries, Australia, Brazil, Latin America, South Africa and other regions. Numerous generic versions of efavirenz, either alone or co-formulated with other drugs, are available.

Efavirenz is also available in a triple-drug combination tablet called Atripla. This tablet is the first once-daily tablet containing a complete HIV treatment regimen. It contains 600mg efavirenz, 200mg emtricitabine (FTC), and 300mg tenofovir. It was approved in the United States in July 2006 and in the European Union and Canada in late 2007. 

Effectiveness

Efavirenz (Sustiva) is a powerful anti-HIV drug that must be taken in combination with other antiretroviral drugs. It has been proven to reduce HIV-1 viral load to below 400 copies/ml within six months in 60 to 80% of people who have not previously taken any HIV treatments. Efavirenz is not active against HIV-2.

Efavirenz has been recommended as a component of first-line antiretroviral treatment since 2002 on the basis of studies showing superior outcomes for people treated with efavirenz-based combinations when compared to protease inhibitor-based treatment or treatment based on nevirapine. (Staszewski) (Tashima) (Arribas) (Schafer) (Robbins) (INITIO) (van Leth) (Riddler)

Recent studies have shown that the integrase inhibitor dolutegravir is more effective than efavirenz, and that the NNRTI rilpivirine is better tolerated (although less effective than efavirenz in people with high viral load, above 100,000 copies/ml).

Taking it

Efavirenz (Sustiva) is dosed at 600mg, taken in the form of three 200mg capsules or one 600mg tablet once a day. The drug should be taken on an empty stomach before going to bed in order to reduce the risk of side-effects. Taking the drug with food may increase drug levels in some people by up to 50%. High-fat meals may increase the absorption of efavirenz, which may in turn increase the risk of side-effects, especially during the early weeks of treatment.

See Atripla for information on taking efavirenz as part of a combination pill with tenofovir and emtricitabine.

Glossary

resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

effectiveness

How well something works (in real life conditions). See also 'efficacy'.

non-nucleoside reverse transcriptase inhibitor (NNRTI)

Non-nucleoside reverse transcriptase inhibitor, the family of antiretrovirals which includes efavirenz, nevirapine, etravirine, doravirine and rilpivirine. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to and block HIV reverse transcriptase (an HIV enzyme), preventing HIV from replicating.

serum

Clear, non-cellular portion of the blood, containing antibodies and other proteins and chemicals.

 

antiretroviral (ARV)

A substance that acts against retroviruses such as HIV. There are several classes of antiretrovirals, which are defined by what step of viral replication they target: nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; integrase (strand transfer) inhibitors.

It is important to take the drug as prescribed in order to maintain the right level of the drug in the blood. If blood levels of the drug fall too low, this will help the development of resistance to efavirenz and may affect future treatment options.

Efavirenz is also available as a solution for use in children and people who cannot take the tablets or capsules.

Side-effects

The commonest side-effects of efavirenz occur in the brain. Trials have shown that 14 to 50% of people who take efavirenz develop side-effects in the first few months of treatment including drowsiness or insomnia, dizziness, vivid dreams and nightmares, confusion, abnormal thinking, impaired concentration, loss of memory, agitation, feeling ‘out-of-sorts’ or ‘stoned’, hallucinations, delusions, euphoria, and depression. (Gallego) Some of these side-effects are attributed to the detrimental impact efavirenz has on sleep.

The existence of the psychiatric side-effects of efavirenz, including depression, suicidal ideation, aggression, paranoia and mania is controversial. Some studies have found no links between these effects and efavirenz use. (Journot) If they are real, however, it is certain that they are rare, although they may be more common in people with a history of psychiatric disorders. (Boly) Only 1% of people in trials discontinued efavirenz due to psychiatric side-effects.

Side-effects are most likely to occur in the first two to four weeks of treatment, after which they tend to diminish markedly. (Clifford) However, there is some evidence that symptoms like mild anxiety and bad dreams may persist in up to half of people for over six months, or even while treatment continues. (Hawkins) (Moyle) (Fumaz) Despite their frequency, most people experience only mild to moderate symptoms and trials indicate that only 3% of people stop taking efavirenz because of side-effects.

The manufacturer currently recommends that efavirenz be taken before going to bed, since the feelings of dizziness and anxiety are likely to be most intense in the hours leading up to the peak in drug level, usually about four hours after dosing. However, up to half of people prefer to take efavirenz in the morning, to avoid bad dreams, disturbed sleep, and morning drowsiness attributed to the drug. (Skeie)

Because of a genetic variation, some people will metabolise efavirenz slower than others. This variation is common among people with a black African heritage and it may increase the risk of side-effects. (Burger) (Haas) (Rodriguez-Novoa)Genetic testing for this variation is not currently available. Therapeutic drug monitoring may be used to identify people who are exposed to high concentrations of efavirenz.

Rash is also common in people taking efavirenz, affecting around a quarter of people in trials. It can usually be controlled using antihistamines and tends to resolve within a month of starting efavirenz-based therapy.

Gynaecomastia (enlargement of the breasts) has been observed in a small number of people taking efavirenz. (Mira) (Qazi) A hypersensitivity reaction to efavirenz has also been reported in two individuals. Symptoms included rash, fever, abdominal pain, diarrhoea, dry cough and jaundice. (Bossi)

Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to efavirenz (Sustiva) may be transmitted or may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug. Even small amounts of transmitted efavirenz-resistant virus may also curtail the drug's effectiveness. If blood levels of the drug fall too low, this will help the development of resistance to efavirenz and may affect future treatment options.

Drug interactions

Although rarely used in combination with other antiretrovirals nowadays, efavirenz alters the levels of most protease inhibitors and usually requires adjusted dosing. Efavirenz is not administered with the other NNRTI drugs etravirine and nevirapine due to elevated side-effect risk. (van Leth)

The following drugs should be avoided when taking efavirenz because the possibility of decreased metabolism when taken with efavirenz could possibly lead to life-threatening adverse events such as cardiac arrhythmias, prolonged sedation, or respiratory distress:  

  • Astemizole (Hispaniola)
  • Bepidril (Visor). Vascor discontinued by manufacturer
  • Cisapride (Repulsed). Discontinued in the US
  • Dihydroergotamine, ergotamine, ergonovine, & ergot derivatives (Cafatine, Ergomar, Migranal)
  • Midazolam (Hyponovel, Versed)
  • Pimozide (Orap)
  • Terfenadine (Triludine, Teldane, Seldane). Drug discontinued in US
  • Triazolam (Halcion) should be avoided because of its decreased serum levels; use of lorazepam, oxazepam, or temazepam may be considered.

Other drugs to be avoided when on efavirenz (Sustiva) include:

  • Amodiaquine (Cameoing, Flavouring), due to risk of elevated liver enzymes
  • Clarithromycin (Claiosip, Klaricid, Klaricid XL, Bioxin) levels reduced and there have been reported high incidences of rash. Use of azithromycin can be considered
  • Gingko biloba can decrease efavirenz levels (Wiegman)
  • Hypericin (St John’s Wort) can reduce efavirenz levels
  • Milk thistle has a possibility of interaction.

The following drugs need to be administered at non-standard doses in people taking efavirenz:

  • Anticoagulants. Warfarin (Coumadin) levels may be increased or decreased. Monitor INR and adjust warfarin as needed.
  • Anticonvulsants. Phenytoin (Epanutin, Dilantin), phenobarbital (Luminol), and carbamazepine (Tegretol) may need to be given at lower doses to prevent reduction in efavirenz level. Anticonvulsant plasma levels should be monitored or possibly use therapeutic drug monitoring for efavirenz. (Robertson) Alternative anticonvulsants to be considered include valproic acid, lamotrigine, levetiracetam, or topiramate.  
  • Antidepressants. Sertraline (Zoloft) levels may be decreased when given with efavirenz.
  • Antifungals. Itraconazole (Sporanox) and ketoconazole (Nizoral) may have decreased plasma concentration. Voriconazole (Vfend) is usually not co-prescribed with efavirenz because of the risk of low voriconazole/elevated efavirenz levels. If drugs needed to be used concomitantly, voriconazole dosing should be increased from 200 to 400mg and given every 12 hours; once-daily dosing of efavirenz should be decreased from 600 to 300mg.
  • Anti-infectives. Rifabutin (Mycobutin) levels are decreased by 35%, so consider dosing rifabutin once daily 450-600mg, or 3 times per week at 600mg, if efavirenz is not being given with a protease inhibitor.(Weiner) (Adult Prevention and Treatment of Opportunistic Infections Guidelines Working Group) Rifampicin (Rifadin, Rimactane) should not be used in people on protease inhibitor-based antiretroviral therapy. As rifampicin decreases efavirenz levels by an average of 25%, individuals at the normal efavirenz dose of 600mg once daily should be monitored for response. In those weighing over 60kg, consider increasing the daily dose to 800mg. Results from the British CHIC study indicated that black ethnicity was associated with higher efavirenz levels and increased weight contributed to lower efavirenz concentrations. (Stöhr) An earlier study in Thai patients, who were mainly under 55kg, found that the 600mg dose of efavirenz was effective. (Manosuthi)
  • Antimalarials. Artemether and mefloquine serum levels may be decreased, so monitoring is needed (i.e. mefloquine serum level, parasite count on blood smear, clinical signs of improvement).
  • Chemotherapy agents paclitaxel tamoxifen, vinblastine, and vincristine may have lessened serum concentrations; drug levels should be monitored.
  • Contraceptives. Ethinyl estradiol may have an interaction with efavirenz. Use of barrier contraception is recommended in addition to oral contraceptives to prevent pregnancy.
  • Immunosuppressants. Cyclosporine (Neoral, Sandimmune), sirolimus, tacrolimus, drugs mainly used after transplant surgery, should be dosed according to serum levels, as each may be decreased when taken with efavirenz. (Tseng)
  • Opioiods. Methadone hydrochloride (Methadose) may need to be given at a higher dose in people taking efavirenz. (Clarke) The dose should be increased in 10mg steps if withdrawal symptoms appear.
  • Statins. Atorvastatin (Lipitor), pravastatin (Pravachol), and simvastatin (Zocor) may need to be given at a higher dose to achieve target lipid goals, but require monitoring to avoid possible toxicity. (Gerber)

Efavirenz may cause a false-positive result if the CEDIA DAU Multi-Level THC assay is used. Other types of tests do not confuse efavirenz and cannabis.

Children

Efavirenz (Sustiva) is approved in the European Union and the United States for use in children with HIV infection aged three years and over. For children who weigh less than 40kg, the dose is adjusted for weight. A syrup formulation is available for children who find capsules difficult to take. Efavirenz has not been evaluated in children under three years of age or below 10kg in weight.

Pregnancy

Efavirenz can be used during pregnancy although experts in different countries and regions have arrived at different conclusions about when it is preferable to use it. Efavirenz is recommended as a preferred first-line drug in World Health Organization guidelines. National guidelines in the United Kingdom recommend newer drugs but do not recommend against the use of efavirenz during pregnancy. European guidelines recommend continuation of efavirenz during pregnancy; for women starting treatment during pregnancy efavirenz may be used if other options are not available. United States guidelines, last updated in 2016, recommend against the use of efavirenz in the first three months of pregnancy.

Previous treatment guidelines warned against the use of efavirenz during pregnancy based on findings from animal studies and a small number of case reports of neural tube defects in infants exposed to efavirenz during the first three months of gestation. (Fundaro)

It is now clear that birth defects do not occur at a higher rate in infants exposed to efavirenz.

A systematic review and meta-analysis of 23 studies, published in 2014, found that treatment with efavirenz during the first three months of pregnancy did not increase the risk of birth abnormalities. Amongst children born to women who received efavirenz in the first trimester, the overall incidence of birth abnormalities was 1.6%, and the prevalence of neural tube defects was 0.05%. Both figures are very close to the ranges reported in the general population in many developed and developing countries. (Ford)

References

Staszewski S 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. New England Journal of Medicine, 341: 1865-1873, 1999.

Tashima K et al. Durable viral suppression on EFV-based HAART: 168 weeks of follow-up. 15th International AIDS Conference, Bangkok, abstract TuPeB4547, 2004.

Arribas JR et al. High effectiveness of efavirenz-based highly active antiretroviral therapy in HIV-1-infected patients with fewer than 100 CD4 cells/ul and opportunistic diseases: the EfaVIP study (efavirenz in very immunosuppressed patients). AIDS, 16: 1554-1556, 2002.

Schafer R et al. Antiretroviral strategies in naive HIV+ subjects: comparison of 4-drug versus sequential 3-drug regimens (ACTG 384). 14th International AIDS Conference, Barcelona, abstract LbOr20B, 2002.

Robbins G et al. Antiretroviral strategies in naive HIV+ subjects: comparisons of sequential 3-drug regimens (ACTG 384). 14th International Conference on AIDS, Barcelona, abstract LbOr20A, 2002.

INITIO Trial Coordinating Committee et al. Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitors, protease inhibitor, or both in INITIO: open-label randomised trial. The Lancet, 368: 287-298, 2006.

van Leth F 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. The Lancet, 363: 1253-1263, 2004.

Riddler SA et al. Class-sparing regimens for initial treatment of HIV-1 infection. New England Journal of Medicine, 358: 2095-2106, 2008.

Gallego L et al. Analyzing sleep abnormailities in HIV-infected patients treated with efavirenz. Clinical Infectious Diseases, 38: 430-432, 2004.

Journot V et al. Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099. Clinical Infectious Diseases, 42: 1790-1799, 2006.

Boly L et al. Depressive symptoms predict increased incidence of neuropsychiatric side-effects in patients treated with efavirenz. Journal of Acquired Immune Deficiency Syndromes, 42: 514-516, 2006.

Clifford DB et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Annals of Internal Medicine, 143: 714-721, 2005.

Hawkins T et al. Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients. HIV Clinical Trials, 6: 187-196, 2005.

Moyle G et al. Changes in sleep quality and brain wave patterns following initiation of an efavirenz-containing triple antiretroviral regimen. HIV Medicine, 7: 243-247, 2006.

Fumaz CR et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. Journal of Acquired Immune Deficiency Syndromes, 38: 560-565, 2005.

Skeie L et al. Can efavirenz be taken in the morning? Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WePe12.3C03, 2005.

Burger D et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. British Journal of Clinical Pharmacology, 61: 148-154, 2006.

Haas D et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult Clinical Trials Group study. AIDS, 18: 2391-2400, 2004.

Rodriguez-Novoa S et al. Influence of 516T>G polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. Clinical Infectious Diseases, 40: 1358-1361, 2005.

Mira JA et al. Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. Antiviral Therapy, 9: 511-517, 2004.

Qazi NA et al. Gynaecomastia without lipodystrophy in HIV-1-seropositive patients on efavirenz: an alternative hypothesis. AIDS, 16: 506-507, 2002.

Bossi P et al. Hypersensitivity syndrome associated with efavirenz therapy. Clinical Infectious Diseases, 30: 227-228, 2000.

Wiegman D-J et al. Interaction of Gingko biloba with efavirenz. AIDS, 23: 1184-85, 2009.

Robertson SM et al. A potentially significant interaction between efavirenz and phenytoin: a case report and review of the literature. Clinical Infectious Diseases, 41: e15-e18, 2005.

Weiner M et al. Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis. Clinical Infectious Diseases, 41: 1343-1349, 2005.

Adult Prevention and Treatment of Opportunistic Infections Guidelines Working Group. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents [June 18 2008 DRAFT version]. Available at: http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf. Accessed (30 November 2008), 2008.

Stöhr W et al. for the UK CHIC Study Factors influencing efavirenz and nevirapine plasma concentration: effect of ethnicity, weight and co-medication. Antiviral Therapy, 13: 675-685, 2008.

Manosuthi W et al. Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results. AIDS, 20: 131-132, 2006.

Tseng A et al. Probable interaction between efavirenz and cyclosporin. AIDS, 16: 505-506, 2002.

Clarke S et al. Managing methadone and non-nucleoside reverse transcriptase inhibitors: guidelines for clinical practice. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 88, 2000.

Gerber JG et al. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin and pravastatin. Results of AIDS Clinical Trials Group 5108 Study. Journal of Acquired Immune Deficiency Syndromes, 39: 307-312, 2005.