title: Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study.
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.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE- 141 86, Stockholm, Sweden.
authors.forename: Jackson K
authors.initials: JK
authors.lastname: Mukonzo
authors.forename: Alphonse
authors.initials: A
authors.lastname: Okwera
authors.forename: Neoline
authors.initials: N
authors.lastname: Nakasujja
authors.forename: Henry
authors.initials: H
authors.lastname: Luzze
authors.forename: Deogratious
authors.initials: D
authors.lastname: Sebuwufu
authors.forename: Jasper
authors.initials: J
authors.lastname: Ogwal-Okeng
authors.forename: Paul
authors.initials: P
authors.lastname: Waako
authors.forename: Lars L
authors.initials: LL
authors.lastname: Gustafsson
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D048588:Benzoxazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology / Q000523:psychology; D006212:Hallucinations / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D001523:Mental Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology / Q000821:virology; D011446:Prospective Studies; D012293:Rifampin / Q000627:therapeutic use; D020921:Sleep Arousal Disorders / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D014454:Uganda / Q000453:epidemiology
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D012293:Rifampin