rifampin and Hallucinations

Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.. Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.. CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.. This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Alleles; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B; Benzoxazines; Body Weight; Case-Control Studies; Cyclopropanes; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2B6; Drug Interactions; Female; Hallucinations; Headache; Humans; Male; Models, Biological; Rifampin; Sex Characteristics; Sleep Wake Disorders; Tuberculosis; Zimbabwe

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.. 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.. 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.. 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.

Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cognitive Dysfunction; Constitutive Androstane Receptor; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Female; Gene Frequency; Hallucinations; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Memory Disorders; Mental Disorders; Prospective Studies; Rifampin; Sleep Arousal Disorders; Tuberculosis; Uganda

Hemodialysis permits a long term survival to patients with End Stage Renal Disease (E.S.R.D.). However the patients ongoing hemodialysis presented a immunodeficiency and a important modification of drugs biodisponibility. Tuberculosis is an endemic disease in our countries. Extrapulmonary tuberculosis is reported from these two cases among 13 patients treated in C.H.U.A. Le Dantec hemodialysis center. Clinical symptoms are not specific bacteria is not found. Diagnosis is obtained by a bundle of arguments. Antituberculosis treatment need to be adjusted in this field. Even if Rifampicine can be administrated at normal dose. The others drugs must be adapted on their clearance and the underlying disease. The two patients presented psychiatrical symptoms motivating a reduction of isoniazide dose witch threshold toxicity is lowered by renal failure state. These observations must increase watchfulness on nephrologist of undeveloping countries, confronted with tuberculosis renewed out break.

Topics: Adolescent; Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Hallucinations; Humans; Isoniazid; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Renal Dialysis; Rifampin; Senegal; Streptomycin; Tuberculosis