Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate.

TitleEffects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate.
Publication TypeJournal Article
Year of Publication2018
AuthorsMacBrayne CE, Marks KM, Fierer DS, Naggie S, Chung RT, Hughes MD, Kim AY, Peters MG, Brainard DM, Seifert SM, Castillo-Mancilla JR, Bushman LR, Anderson PL, Kiser JJ
JournalJ Antimicrob Chemother
Volume73
Issue8
Pagination2112-2119
Date Published2018 Aug 01
ISSN1460-2091
Abstract

Background: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions.

Objectives: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate.

Methods: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS.

Results: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment.

Conclusions: These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.

DOI10.1093/jac/dky146
Alternate JournalJ. Antimicrob. Chemother.
PubMed ID29746648
PubMed Central IDPMC6054189
Grant ListUM1 AI069503 / AI / NIAID NIH HHS / United States
UM1 AI069432 / AI / NIAID NIH HHS / United States
UM1 AI069471 / AI / NIAID NIH HHS / United States
UM1 AI069534 / AI / NIAID NIH HHS / United States
R01 DA040499 / DA / NIDA NIH HHS / United States
P30 AI045008 / AI / NIAID NIH HHS / United States
UM1 AI069412 / AI / NIAID NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
U01 AI069432 / AI / NIAID NIH HHS / United States
UM1 AI069496 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
UM1 AI069465 / AI / NIAID NIH HHS / United States
UM1 AI069419 / AI / NIAID NIH HHS / United States
U01 AI069419 / AI / NIAID NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
U01 AI069471 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States