Safety and Pharmacokinetics of Double-Dose Lopinavir/Ritonavir + Rifampin vs. Lopinavir/Ritonavir + Daily Rifabutin for Treatment of HIV-TB Coinfection.

BACKGROUND Protease inhibitor-based antiretroviral therapy (ART) may be used in resource-limited settings in persons with HIV-TB. Data on safety, pharmacokinetics/pharmacodynamics (PK/PD), and HIV-TB outcomes for lopinavir/ritonavir (LPV/r) used with rifampin (RIF) or rifabutin (RBT) are limited. METHODS We randomized adults with HIV-TB from July 2013 to February 2016 to: Arm A, LPV/r 400mg/100mg twice daily+RBT 150mg/day; Arm B, LPV/r 800mg/200mg twice daily+RIF 600mg/day; or Arm C, LPV/r 400mg/100mg twice daily+raltegravir (RAL) 400mg twice daily+RBT 150mg/day; all received two nucleoside reverse transcriptase inhibitors and other TB drugs. PK visits occurred on day 12+2. Within-arm HIV-TB outcomes were summarized using proportions and 95% confidence intervals; PK was compared using Wilcoxon tests. RESULTS Among 71 participants, 52% were women; 72% Black; 46% Hispanic; median age 37 years; median CD4 + 130 cells/mm 3; median HIV-1 RNA 4.6 log10 copies/mL; 46% had confirmed TB. LPV concentrations were similar across arms. Pooled LPV AUC12 (157,203 h*ng/mL) and Ctrough (9,876 ng/mL) were similar to historical controls; RBT AUC24 (7,374 h*ng/mL) and Ctrough (208 ng/mL) were higher. Grade 3 uveitis due to RBT occurred in three participants; three in Arm C had RBT Cmax <250ng/mL. Proportions with week 48 HIV-1 RNA <400 copies/mL were 58%, 67%, and 61% and week 8 sputum conversion were 88%, 82%, and 70%, respectively, in Arms A, B, and C. CONCLUSIONS Double-dose LPV/r+RIF and LPV/r+RBT 150mg/day had acceptable safety, PK and TB outcomes; viral suppression was suboptimal unrelated to PK. Faster RBT clearance and low Cmax in three participants on RBT+RAL requires further study.