Dear Sirs,

I read with great interest the recent article by Nachega et al. (2013). Interestingly, one common cause of psychiatric symptoms in HIV patients that is often overlooked is efavirenz therapy.

Nearly 13% of patients on efavirenz therapy discontinue the drug secondary to its adverse psychiatric effects (Hasse et al. 2005). Psychiatric symptoms are reported by more than half of all patients on efavirenz therapy. Pérez-Molina (2002) have reported a much higher rate of psychiatric symptoms, in almost 73% of HIV patients on efavirenz therapy. CYP2B6-G516T polymorphisms have a significant influence on the clearance of efavirenz. For instance, Lowenhaupt et al. (2007) reported the case of a patient with a heterozygous gene polymorphism of CYP2B6-G516T, who developed accentuated efavirenz concentrations leading to subsequent psychosis. Among these polymorphisms, 36% are GG and 23% are of the TT subtype. Significantly, higher efavirenz levels have been noted in patients with TT polymorphisms. As a result, patients with TT polymorphisms are more predisposed to develop psychiatric symptoms (van Twillert et al. 2005). Efavirenz clearance is genetically attenuated in Afro-Americans, especially women, and thereby this group is at a higher risk of developing efavirenz-induced psychosis. Efavirenz-induced psychosis has been reported in patients as young as 12 years of age. The general consensus is that efavirenz may alter cytokine levels that may contribute to the development of these psychiatric symptoms (Salter & Patel 2009). The CD4 lymphocyte counts as well as the ‘viral load’ have a significant influence on the severity of these psychiatric effects. Interestingly, coinfection with hepatitis B greatly accentuates the risk of developing psychiatric adverse effects.

Psychiatric symptoms usually appear after the first dose and progressively get worse. Psychosis is seen in 2% of patients on efavirenz therapy (Wintergerst et al. 2008). Interestingly, CYP2B6-G516T polymorphisms also influence the appearance and incidence of side effects of efavirenz. For instance, 30% of patients on efavirenz therapy report increased irritability. Patients may present with schizophreniform disease. Psychotic symptoms may appear as much as 3 years after initiation of efavirenz therapy (Velasco et al. 2011). Some patients may present with accentuated anxiety. Paranoid hallucinations as well as delusions are often reported. The incidence of psychosis among children on efavirenz therapy is around 3.0%. Homicidal acts may worsen the scenario. Gutiérrez et al. (2005) have also reported the development of obsessive symptoms secondary to efavirenz therapy. Both insomnia (28.3%) and hypersomnolence (25%) have been reported (Zalila et al. 2010). Nightmares and abnormal dreams are increased in frequency and are reported by 48.3% of the patients. Wintergerst et al. (2008) reported that 15.1% of children on efavirenz therapy report concentration problems. The corresponding number for adults is 26.7% (Sabbatani et al. 2002). 30% of the patients report increased anxiety and nervousness. Symptoms are most marked 2 weeks after initiation of therapy and usually last for 4 weeks. Complications noted later during efavirenz therapy include depression. Mildly impaired psychological alterations may persist for as long as 2 years. Simultaneous use of illicit drugs accentuates the propensity of developing psychiatric symptoms.

Given the high incidence of psychiatric complications, all patients to be started on efavirenz therapy should be evaluated for any psychiatric abnormalities. While on efavirenz therapy, serum levels of efavirenz should be routinely monitored. Interestingly, cyproheptadine has recently been shown to be effective in ameliorating and mitigating the neuropsychiatric symptoms of efavirenz therapy (Mills et al. 2013). Cyproheptadine has a significant impact on decreasing efavirenz-induced accentuation of both the ‘Beck Depression Scale’ scores as well as the ‘Hamilton Depression Rating Scale’ scores. A similar reduction is seen in the ‘Positive and Negative Syndrome Scale’ scores. In addition, before initiating efavirenz therapy, cytochrome P450 gene variant testing is advised (Dabaghzadeh et al. 2012).

These reports illustrate the significant psychiatric side effects of efavirenz and the need to watch out for these symptoms.


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  • Dabaghzadeh F, Khalili H, Ghaeli P & Dashti-Khavidaki S (2012) Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz. Expert Opinion on Pharmacotherapy 13, 26132624.
  • Gutiérrez F, Navarro A, Padilla S et al. (2005) Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clinical Infectious Diseases 41, 16481653.
  • Hasse B, Gunthard HF, Bleiber G & Krause M (2005) Efavirenz intoxication due to slow hepatic metabolism. Clinical Infectious Diseases 40, e22e23.
  • Lowenhaupt EA, Matson K, Qureishi B, Saitoh A & Pugatch D (2007) Psychosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz. Clinical Infectious Diseases 45, e128e130.
  • Mills A, Antinori A, Clotet B et al. (2013) Neurological and psychiatric tolerability of rilpivirine (TMC278) vs. efavirenz in treatment-naive, HIV-1-infected patients at 48 weeks. HIV Medicine 14, 391400.
  • Pérez-Molina JA (2002) Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. HIV Clin Trials 3, 279286.
  • Nachega JB, Mutamba B, Basangwa D et al. (2013) Severe mental illness at ART initiation is associated with worse retention in care among HIV-infected Ugandan adults. Tropical Medicine and International Health 18, 5357.
  • Sabbatani S, Fulgaro C & Rosticelli E (2002) Efficacy of efavirenz in a mixed population of patients. Identification of drop-out causes. Infez Med 10, 163168.
  • Salter E & Patel AS. (2009) Neuropsychiatric sequelae in an efavirenz treated patient with hepatitis B. BMJ Case Reports 2009. doi: 10.1136/bcr.07.2009.2061.
  • van Twillert G, van Santen G & Godfried MH (2005) Severe psychosis in an African woman due to the antiretroviral agent efavirenz. Nederlands Tijdschrift voor Geneeskunde 149, 26872689.
  • Velasco M, Pareja JA, Losa JE, Valverde JF, Espinosa A & Gujarro C (2011) Dream changes following initiation of efavirenz treatment. Medicina Clínica 136, 103105.
  • Wintergerst U, Hoffmann F, Jansson A et al. (2008) Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. Journal of Antimicrobial Chemotherapy 61, 13361339.
  • Zalila H, Elloumi H, Gaha N, Ghachem R, Ghazali I & Boussetta A (2010) Acute psychosis under efavirenz in a HIV patient. La Tunisie Médicale 88, 119121.