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.1 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.2 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.3 Only 1% of patients 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.4 However, there is some evidence that symptoms like mild anxiety and bad dreams may persist in up to half of patients for over six months, or even while treatment continues.5 6 7 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 patients prefer to take efavirenz in the morning, to avoid bad dreams, disturbed sleep, and morning drowsiness attributed to the drug.8

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.9 10 11 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.

In ACTG 5142, while efavirenz suppressed viral load for longer, those who took the drug were almost twice as likely to experience fat loss in the face or limbs compared to those who took Kaletra.12

Lipoatrophy, defined as a 20% loss of limb fat at week 96, was experienced by 32% of the efavirenz + 2 NRTI group, 17% of the Kaletra + 2 NRTI group, and 9% of the Kaletra/efavirenz group.

Compared to EFV, LPV had less lipoatrophy when given with NRTI. When lipoatrophy incidence was analysed according to pairings of drugs, it was evident that tenofovir recipients who received efavirenz were more likely to develop lipoatrophy (12%) than those who received Kaletra (6%). Similarly, AZT recipients who received efavirenz were also at greater risk of lipoatrophy (40% vs 16% for Kaletra recipients). The difference was less pronounced for d4T recipients (51% for efavirenz, 33% for Kaletra).

After 96 weeks those in the LPV + EFV nucleoside-sparing arm had experienced an average 18% gain in limb fat (around 1kg), compared to a 9.8% gain in the Kaletra + 2 NRTIs group and a gain of 1.4% in the efavirenz group.

Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but cholesterol elevations between the Kaletra and efavirenz arms were similar. The increase in HDL cholesterol was significantly greater in the Kaletra /efavirenz nucleoside-sparing arm.

Elevated liver enzymes were reported in 2% of the patients taking efavirenz in study 006.13 These are more common in patients co-infected with hepatitis B or C.

Less common side-effects of efavirenz include headache, alcohol intolerance, fever, aches, pains and fatigue, fluid retention in the hands and feet, dry mouth, elevated lipid levels, pancreatitis, skin problems, asthma and changes to vision and taste. Interestingly, reports of lipid elevations have included rises in high-density lipoprotein (HDL) or ‘good’ cholesterol, particularly in people with a genetic polymorphism in the multidrug resistance gene 1.14 15 However, levels of total cholesterol also increase, resulting in a small net increase in the ratio of total to HDL cholesterol.16 This study also found that efavirenz causes elevations in triglyceride levels.

Gynaecomastia (enlargement of the breasts) has been observed in a small number of patients taking efavirenz.17 18 19 A hypersensitivity reaction to efavirenz has also been reported in two individuals. Symptoms included rash, fever, abdominal pain, diarrhoea, dry cough and jaundice.20 In the second case, the hypersensitivity reaction also involved the lungs.21 One case of a urinary stone caused by efavirenz has also been reported.22 A case of anaemia due to the breakdown of red blood cells has also been attributed to efavirenz treatment.23

References

  1. Gallego L et al. Analyzing sleep abnormailities in HIV-infected patients treated with efavirenz. Clin Infect Dis 38: 430-432, 2004
  2. Journot V et al. Use of efavirenz is not associated with a higher risk of depressive disorders: a sybstudy of the randomized clinical trial ALIZE-ANRS 099. Clin Infect Dis 42: 1790-1799, 2006
  3. Boly L et al. Depressive symptoms predict increased incidence of neuropsychiatric side-effects in patients treated with efavirenz. J Acquir Immune Defic Syndr 42: 514-516, 2006
  4. Clifford DB et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 143: 714-721, 2005
  5. Hawkins T et al. Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients. HIV Clin Trials 6: 187-196, 2005
  6. Moyle G et al. Changes in sleep quality and brain wave patterns following initiation of an efavirenz-containing triple antiretroviral regimen. HIV Med 7: 243-247, 2006
  7. Fumaz CR et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr 38: 560-565, 2005
  8. 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
  9. 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. Br J Clin Pharmacol 61: 148-154, 2006
  10. Haas D et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult Clinical Trials Group study. AIDS 18: 2391-2400, 2004
  11. 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. Clin Infect Dis 40: 1358-1361, 2005
  12. Haubrich R et al. Metabolic outcomes of ACTG 5142: a prospective randomised phase III trial of NRTI, PI- and NNRTI-sparing regimens for initial treatment of HIV-1 infection. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 38, 2007
  13. Tashima K et al. Durable viral suppression on EFV-based HAART: 168 weeks of follow-up. 15th International AIDS Conference, Bangkok, abstract TuPeB4547, 2004
  14. Tashima K et al. Lack of clinical lipodystrophy in patients receiving efavirenz + NRTIs in study 006. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 1301, 1999
  15. Alonso-Villaverde C et al. The efavirenz-induced increase in HDL-cholesterol is influenced by the multidrug resistance gene 1 C3435T polymorphism. AIDS 19: 341-342, 2005
  16. Van Leth F et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naïve patients infected with HIV-1. PLoS Med 1: e19, 2004
  17. Jover F et al. Efavirenz-associated gynecomastia: five cases and review of the literature. Breast J 10: 244-246, 2004
  18. Mira JA et al. Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. Antivir Ther 9: 511-517, 2004
  19. Qazi NA et al. Gynaecomastia without lipodystrophy in HIV-1-seropositive patients on efavirenz: an alternative hypothesis. AIDS 16: 506-507, 2002
  20. Bossi P et al. Hypersensitivity syndrome associated with efavirenz therapy. Clin Infect Dis 30: 227-228, 2000
  21. Behrens GMN et al. Pulmonary hypersensitivity reaction induced by efavirenz. Lancet 357: 1503-1504, 2001
  22. Wirth GJ et al. Efavirenz-induced urolithiasis. Urol Res (online edition), 2006
  23. Freercks RJ et al. Haemolytic anaemia associated with efavirenz. AIDS 20: 1212-1213, 2006
This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.