Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine

Abstract

Background: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB).

Methods: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target.

Results: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%.

Conclusions: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment.

Clinical trials registration: NCT02410772.

Keywords: HIV/AIDS; efavirenz; pharmacokinetics; rifapentine; tuberculosis.

Conflict of interest statement

Potential conflicts of interest. The authorship team members have declared (below or attached) any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team. N. M. reports a grant to the institution for pneumonia research from Pfizer and a subaward to collect specimens to validate a TB diagnostic from Roche. L. M. reports grants or contracts from Merck Sharpe & Dohme (institution received clinical trial fees), ViiV Healthcare (institution received clinical trial fees), Kowa Pharmaceuticals America (pharmaceutical support on protocol), and Sanofi-Aventis (pharmaceutical support on protocol) outside of the submitted work. S. S. reports research grant support to the institution from ViiV Healthcare outside of the submitted work and support for attending meetings and/or travel from the National Institutes of Health (NIH). C. V. F. reports being a member of the Safety Monitoring Committee for Division of Microbiology and Infectious Diseases (DMID), NIAID, NIH, for 2 protocols on (1) an influenza virus challenge study and (2) a safety and pharmacokinetics of single doses of an antifungal, VT-1598 (no payments are made to institution or personally for service on this SMC). R. E. C. reports consulting fees from Sanofi. U. L. reports funding support for travel to ACTG Annual Network Meeting from AIDS Clinical Trials Group. A. A. V. reports working with a group at CDC that perform TB trials. The group has collaborated with pharmaceutical partners. Sanofi collaborated in Study 31/A5349 and provided support for testing PK of TB drugs, and provided drugs for the trial. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Efavirenz (EFV) sampling times (hours post dose) by week (A), EFV concentrations by week (B), EFV apparent oral clearance (CL/F) pre/post rifapentine (RPT) and isoniazid (H) and during RPT/H treatment (C), shown for EFV1 (top row) and EFV2 (bottom row).