Administration of efavirenz (600 mg/day) with rifampicin results in highly variable levels but excellent clinical outcomes in patients treated for tuberculosis and HIV.
OBJECTIVE
Pharmacokinetic interactions between rifampicin and antiretroviral therapy (ART), including efavirenz, are problematic and need to be better defined to determine proper dose and to be correlated with short-term and long-term clinical outcomes.


METHODS
Consenting patients with smear-positive pulmonary TB and HIV received once daily didanosine + lamivudine + efavirenz (600 mg), with rifampicin-containing TB regimen by directly observed therapy and self-administration at TB therapy completion. Trough efavirenz levels were measured by HPLC at 1, 2, 4 and 6 months while on rifampicin and after discontinuation. HIV and TB outcomes were monitored.


RESULTS
Twenty African patients were enrolled [15 female, mean age 31 years, baseline weight 59.4 kg (range 45-97), viral load 5.75 log10 copies/mL and CD4 230 cells/mm3]. Seventy-two efavirenz concentrations were available from 19 patients (58 on, 14 after rifampicin). The geometric mean efavirenz concentration was 1730 ng/mL (range 354-27,179) on and 1377 ng/mL (range 572-3975) off rifampicin (P = 0.55). Inter-subject variability in efavirenz concentrations was greater on rifampicin (CV 157% versus 58% off) with relatively consistent intra-subject variation over time (median CV 24%). Over half of patients had efavirenz concentrations above or below the expected therapeutic range (1000-4000 ng/mL). Efavirenz levels were not predicted by weight or gender and were not associated with HIV clinical outcomes. Overall 80% of patients had non-detectable viral loads at 6 months and 65% at 21 months with a cumulative CD4 cell increase of 196 cells/mm3.


CONCLUSIONS
In this longitudinal study, despite wide variability in plasma efavirenz concentrations during rifampicin administration, excellent clinical outcomes were obtained. In African patients treated for HIV and TB, our data support the routine use of efavirenz at 600 mg/day when receiving rifampicin.
Friedland
Gerald
G
Yale University School of Medicine AIDS Program, New Haven, CT 06510-2483, USA. Gerald.friedland@yale.edu
Khoo
Saye
S
Jack
Christopher
C
Lalloo
Umesh
U
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000627:therapeutic use; D048588:Benzoxazines; D018791:CD4 Lymphocyte Count; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D016049:Didanosine / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D008137:Longitudinal Studies; D008297:Male; D010078:Oxazines / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000188:drug therapy*; D019562:Viral Load
D000480:Alkynes; D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D019259:Lamivudine; C098320:efavirenz; D016049:Didanosine; D012293:Rifampin