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Open Access Highly Accessed Research article

Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study

Jackson K Mukonzo12, Alphonse Okwera3, Neoline Nakasujja4, Henry Luzze3, Deogratious Sebuwufu5, Jasper Ogwal-Okeng2, Paul Waako2, Lars L Gustafsson1 and Eleni Aklillu1*

Author Affiliations

1 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE- 141 86, Stockholm, Sweden

2 Department of Pharmacology & Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda

3 Department of Internal Medicine, College of Health Sciences, Makerere University, Kampala, Uganda

4 Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda

5 School of Public Health, College of Health Sciences, Makerere University, Kampala, Uganda

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BMC Infectious Diseases 2013, 13:261  doi:10.1186/1471-2334-13-261

Published: 4 June 2013

Abstract

Background

HIV infection, anti-tuberculosis and efavirenz therapy are associated with neuropsychological effects. We evaluated the influence of rifampicin cotreatment, efavirenz pharmacokinetics and pharmacogenetics on neuropsychiatric disorders in Ugandan HIV patients with or without tuberculosis coinfection.

Methods

197 treatment naïve Ugandan HIV patients, of whom 138 were TB co-infected, enrolled prospectively and received efavirenz based HAART. TB-HIV confected patients received concomitant rifampicin based anti-TB therapy. Genotypes for CYP2B6 (*6, *11), CYP3A5 (*3, *6, *7), ABCB1 (c.3435C>T and c.4036 A/G rs3842), CYP2A6 (*9, *17) and NR1I3 rs3003596 T/C were determined. Efavirenz plasma concentrations were serially quantified at 3rd day, 1st, 2nd, 4th, 6th, 8th and 12th weeks during therapy. Efavirenz neuropsychiatric symptoms were evaluated in terms of sleep disorders, hallucinations and cognitive effects at baseline, at two and twelve weeks of efavirenz treatment using a modified Mini Mental State Examination (MMSE) score.

Results

During the first twelve weeks of ART, 73.6% of the patients experienced at least one efavirenz related neuropsychiatric symptom. Commonest symptoms experienced were sleep disorders 60.5% (n=124) and hallucination 30.7% (n=63). Neuropsychiatric symptoms during HAART were significantly predicted by efavirenz plasma concentrations consistently. Rifampicin cotreatment reduced plasma efavirenz concentrations significantly only during the first week but not afterwards. There was no significant difference in the incidence of neuropsychiatric symptoms between patients receiving efavirenz with or without rifampicin cotreatment. CYP2B6*6 and ABCB1 c.4036 A/G genotype significantly predicted efavirenz concentrations. The tendency of CYP2B6*6 genotype association with higher incidence of having vivid dream (p=0.05), insomnia (p=0.19) and tactile hallucination (p=0.09) was observed mainly at week-2.

Conclusions

Efavirenz related neuropsychiatric symptoms are common among Ugandan HIV patients receiving ART and is mainly predicted by higher efavirenz plasma concentrations and CYP2B6 genotype but not by rifampicin based anti-TB co-treatment.

Keywords:
Efavirenz; Neuropsychiatric toxicity; Rifampicin; CYP2B6; HIV; Tuberculosis; CNS; Antiretroviral therapy; Ugandans