Central nervous system (CNS) side effects (dizziness, insomnia, impaired concentration, abnormal or vivid dreams, and hallucinations) are most common at the start of treatment and usually diminish in two to four weeks. Bedtime dosing on an empty stomach can help reduce symptoms. Less common psychiatric symptoms (catatonia, depression, suicidal thoughts or actions, aggression, paranoid/manic reactions) may also occur. A 2014 study reviewed four previously published AIDS Clinical Trials Group (ACTG) studies regarding efavirenz and suicidal ideation and re-emphasized efavirenz has an association with suicidality (reported suicidal ideation or attempted or completed suicide), and should be used with caution in people with severe or uncontrolled depression and/or a history of suicidality. It is recommended for anyone on a regimen containing efavirenz to be regularly screened for depression and suicidality. Additional side effects may include rash (incidence of up to 26% of adults and 32% of pediatric patients), nausea, vomiting, diarrhea, fever, and gynecomastia (breast development in men). Rash among children is more common and more severe. Efavirenz may raise levels of triglycerides (fat in the blood) and cholesterol. Efavirenz can cause a false positive for marijuana on certain drug tests. A more specific confirmatory test can be done. A link to birth defects in humans was not supported by meta-analyses. Individuals in their first trimester of pregnancy are recommended to continue taking efavirenz as long as their viral load remains undetectable; however, efavirenz should only be used if the potential benefit outweighs the potential risk, as when other treatment options are not available. Because of the association with suicidality and neuropsychiatric effects, it is also recommended to screen for antenatal and postpartum depression in pregnant individuals with HIV who are taking a regimen containing efavirenz. Regular monitoring for increased liver enzyme levels is recommended initially and during treatment for people with hepatitis B/C or liver disease.

Do not take with midazolam, pimozide, ergot derivatives, St. John’s wort, or triazolam. May affect warfarin levels. Can decrease levels of buprenorphine and methadone—monitor for withdrawal. It is not recommended to be taken with Sunlenca, since it’s expected to lower Sunlenca levels by more than 50%. Increase Kaletra to two 200/50 mg tablets + one 100/25 mg tablet twice daily (total 500/125 mg twice daily) (or 520/130 mg twice daily for oral solution) with food when taken with Sustiva. Kaletra cannot be taken once daily with Sustiva. When taken with Tivicay, increase the Tivicay dose to 50 mg twice daily. People who are treatment-experienced should not take Reyataz with Sustiva, but for those who are treatment-naïve, Reyataz once-daily dose should be 400 mg boosted with Norvir. Increase Selzentry to 600 mg twice daily. Increase the Sustiva dose to 800 mg once daily with rifampin for people weighing 110 pounds (50 kg) or more. Rifabutin can be used as an alternative, but dose adjustment is needed. Should not be used with abacavir and lamivudine in people with baseline HIV viral load over 100,000 copies/mL due to increased risk for virologic failure in this group. When taken with carbamazepine, phenobarbital, or phenytoin, periodic monitoring of anticonvulsant and Sustiva levels should be done or alternative antiseizure drugs, such as levetiracetam, should be considered. May decrease effectiveness of birth control pills; consider the use of other contraceptives. Closer monitoring and dose adjustments may be required with posaconazole (avoid unless benefit outweighs potential risk) and itraconazole. The dose of voriconazole should be increased to 400 mg every 12 hours and the Sustiva dose should be decreased to 300 mg once daily using capsules; tablets should not be broken. Monitor effectiveness of clarithromycin or consider using azithromycin instead. Levels of immunosuppressants should be monitored when starting or stopping Sustiva. Cardizem, atorvastatin, pravastatin, and simvastatin doses may need to be adjusted. Titrate dose of bupropion and sertraline based on clinical response. Should not be taken with other medications that prolong QT interval (these abnormal heart rhythms can make the heart stop) or medications with a known risk for torsades de pointes. No dose adjustment with Harvoni. Don’t take with Epclusa or Zepatier. Tell your provider or pharmacist about all medications, herbals, and supplements you are taking or thinking of taking, prescribed or not, as there are other drug interactions that are not listed here.

If you can’t sleep, ask your doctor about gradually adjusting the timing of your dose until it’s taken during the day. A rare genetic trait affecting drug metabolism of Sustiva, leading to a higher rate of side effects, occurs more in African Americans. In pediatric HIV guidelines, Sustiva was downgraded in 2017 from “preferred” to an “alternative” component of an initial regimen for children ages 3–12 years. For individuals with HIV-2, commonly found in some other countries, an NNRTI would not be recommended as HIV-2 is inherently resistant to NNRTIs. Efavirenz is found in the single-tablet regimens Atripla, Symfi, and Symfi Lo.

Dr. Melanie Thompson:

Efavirenz-based regimens are no longer used by most providers and are not recommended by HHS or IAS-USA guidelines due to multiple side effects, many of them affecting the central nervous system, including suicidality (see Atripla, Symfi and Symfi Lo). It also raises cholesterol and triglycerides, and has substantial drug-drug interactions that must be managed. Also, efavirenz should be taken on an empty stomach for best absorption. When used, it should only be given with TDF or TAF + FTC or 3TC. There is little rationale for prescribing efavirenz-based regimens at this time. Efavirenz may be given during pregnancy, but data from IMPAACT 2010 show more frequent growth stunting with efavirenz than with dolutegravir, and dolutegravir is now preferred.

Activist Joey Wynn:

Causes serious side effects such as nightmares, depression, and suicidal ideation, making it difficult to tolerate. It must be taken on an empty stomach. Given other available options, Sustiva is not an obvious first choice for most people.