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SAFETY AND PHARMACOKINETICS OF DOUBLE-DOSE LOPINAVIR/RITONAVIR + RIFAMPIN VERSUS LOPINAVIR/RITONAVIR + DAILY RIFABUTIN FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS-TUBERCULOSIS COINFECTION
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Harvard T.H. Chan School of Public Health. Center for Biostatistics in AIDS Research. Boston, Massachusetts, USA.
Enhancing Care Foundation. Durban International Clinical Research Site. Durban, South Africa.
University of Nebraska Medical Center. UNMC Center for Drug Discovery. Omaha, Nebraska, USA.
Harvard T.H. Chan School of Public Health. Center for Biostatistics in AIDS Research. Boston, Massachusetts, USA.
University of Nebraska Medical Center. UNMC Center for Drug Discovery. Omaha, Nebraska, USA.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of the Witwatersrand. Faculty of Health Sciences. School of Clinical Medicine. Department of Internal Medicine. Clinical HIV Research Unit. Johannesburg, South Africa.
University of California. Antiviral Research Center. San Diego, California, USA.
Enhancing Care Foundation. Durban International Clinical Research Site. Durban, South Africa.
University of Nebraska Medical Center. UNMC Center for Drug Discovery. Omaha, Nebraska, USA.
Harvard T.H. Chan School of Public Health. Center for Biostatistics in AIDS Research. Boston, Massachusetts, USA.
University of Nebraska Medical Center. UNMC Center for Drug Discovery. Omaha, Nebraska, USA.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of the Witwatersrand. Faculty of Health Sciences. School of Clinical Medicine. Department of Internal Medicine. Clinical HIV Research Unit. Johannesburg, South Africa.
University of California. Antiviral Research Center. San Diego, California, USA.
Abstract
Background: Protease inhibitor-based antiretroviral therapy may be used in resource-limited settings in persons with human immunodeficiency virus and tuberculosis (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 400 mg/100 mg twice daily + RBT 150 mg/day; arm B, LPV/r 800 mg/200 mg twice daily + RIF 600 mg/day; or arm C, LPV/r 400 mg/100 mg twice daily + raltegravir (RAL) 400 mg twice daily + RBT 150 mg/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% CIs; PK were compared using Wilcoxon tests.
Results: Among 71 participants, 52% were women; 72% Black; 46% Hispanic; median age, 37 years; median CD4+ count, 130 cells/mm3; median HIV-1 RNA, 4.6 log10 copies/mL; 46% had confirmed TB. LPV concentrations were similar across arms. Pooled LPV AUC12 (157 203 hours × ng/mL) and Ctrough (9876 ng/mL) were similar to historical controls; RBT AUC24 (7374 hours × ng/mL) and Ctrough (208 ng/mL) were higher, although 3 participants in arm C had RBT Cmax <250 ng/mL. Proportions with week 48 HIV-1 RNA <400 copies/mL were 58%, 67%, and 61%, 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; HIV suppression was suboptimal but unrelated to PK. Faster RBT clearance and low Cmax in 3 participants on RBT+RAL requires further study.
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