Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention.

TitleEfavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention.
Publication TypeJournal Article
Year of Publication2015
AuthorsPodany AT, Bao Y, Swindells S, Chaisson RE, Andersen JW, Mwelase T, Supparatpinyo K, Mohapi L, Gupta A, Benson CA, Kim P, Fletcher CV
Corporate AuthorsAIDS Clinical Trials Group A5279 Study Team
JournalClin Infect Dis
Volume61
Issue8
Pagination1322-7
Date Published2015 Oct 15
ISSN1537-6591
KeywordsAdministration, Oral, Adult, Anti-HIV Agents, Antitubercular Agents, Benzoxazines, Drug Therapy, Combination, Female, HIV Infections, HIV-1, Humans, Isoniazid, Male, Reverse Transcriptase Inhibitors, Rifampin, RNA, Viral, Tuberculosis
Abstract

BACKGROUND: Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis.

METHODS: Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8.

RESULTS: Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8.

CONCLUSIONS: The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression.

CLINICAL TRIALS REGISTRATION: NCT 01404312.

DOI10.1093/cid/civ464
Alternate JournalClin. Infect. Dis.
PubMed ID26082504
PubMed Central IDPMC4583578
Grant ListP30 AI094189 / AI / NIAID NIH HHS / United States
UM AI069423 / AI / NIAID NIH HHS / United States
UM1 AI068632 / AI / NIAID NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI069399 / AI / NIAID NIH HHS / United States
UM1 AI069424 / AI / NIAID NIH HHS / United States
UM1 AI069432 / AI / NIAID NIH HHS / United States
UM1 AI069438 / AI / NIAID NIH HHS / United States
UM1 AI069453 / AI / NIAID NIH HHS / United States
UM1 AI069456 / AI / NIAID NIH HHS / United States
UM1 AI069463 / AI / NIAID NIH HHS / United States
UM1 AI069463 / AI / NIAID NIH HHS / United States
UM1 AI069477 / AI / NIAID NIH HHS / United States
UM1 AI069481 / AI / NIAID NIH HHS / United States
UM1 AI069481 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States