891     Efavirenz Levels and Clinical Outcomes in Patients with TB and HIV Treated Concomitantly with ART and Rifampin-containing TB Regimen Gerald Friedland*1,2, C Jack2, S Khoo3, U Lalloo2, and V Naidoo2 1Yale Univ, New Haven, CT, USA; 2Nelson R Mandela Sch of Med, Univ KwaZulu Natal, Durban, South Africa; and 3Univ of Liverpool, UK

Background:  Integration of tuberculosis (TB) and antiretroviral therapies (ART) could improve the outcome of both diseases. Phamacokinetic interactions between rifampin (RIF) and ART, proper dose, and clinical consequences must be defined. We monitored efavirenz (EFV) levels during and after TB therapy and correlated results with clinical outcomes in a pilot study of integrating TB therapy and ART in Durban, South Africa.

Methods:  Consenting patients with smear⁺ pulmonary TB and HIV⁺ received once-daily didanosine (ddI)+lamivudine (3TC)+EFV (600 mg), with RIF-containing TB regimen by directly observed therapy (DOT). and self-administration at TB therapy completion. Trough EFV levels were measured by HPLC at baseline and 1, 2, 4, and 6 months on RIF and 15 months after RIF was discontinued (therapeutic range 1000to 4000 ng/mL).

Results:  Of 20 patients enrolled, 17 completed combined RIF+EFV therapy (15 female, mean age 31 years, baseline weight 59.4 kg [range 45 97], viral load 5.75 log₁₀ CD4 230 cells/mm³⁾, 16 (80%) achieved an undetectable viral load, CD4 cell count increase 148 cells/mm³, and weight increase of 3.7 kg; 19 (95%) were cured of TB. Three patients remained viremic, 2 with 3TC- and EFV-resistance and 7 (35%) had neuropsychiatric symptoms. After a mean of 15 months of self-administration, 82% remained on ART, 65% had an undetectable viral load and a total mean weight gain of 7.4 kg. All EFV levels (n = 71) median 1339 ng/mL (range 354 to 27,179), on RIF (n = 58) median 1401 ng/mL (range), off RIF (n = 13) median 1479 ng/mL (range 572 to 3975) (p = ns). There was substantial intersubject variation, but intrasubject levels were consistent over time. Four patients had repeatedly high EFV levels on RIF (3 normalized off RIF); 6 repeatedly low levels (4 normalized off RIF); 6 low normal levels (4 normalized off RIF). EFV levels were associated with weight:  < 60 kg (n = 31) median 2101 ng/mL (range 354 to 27,179), > 60 kg (n = 34) median 1401 ng/mL (445 to 10,311) (p < 0.05) < 60 kg, 26% > 4000 ng/mL, > 60 kg 12% > 4000 ng/mL (p < 0.05), but not with a percentage < 1000 ng/mL; gender; ART efficacy; failure; ART resistance or toxicities (although both patients with levels >10,000 ng/mL had neuropsychiatric toxicity).

Conclusions:  Treatment for TB and HIV with RIF and EFV 600 mg/day, was efficacious as measured by viral load, CD4 and weight gain. EFV levels were significantly affected by weight and influenced by RIF, but did not predict either clinical efficacy or toxicity. The wide variability in EFV concentrations suggests that 600 mg/day is adequate in this population, except in patients who weigh > 60 kg, in whom increasing the dose should be considered.

Keywords: Tuberculosis; Antiretrovirals; efavirenz/rifampin