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

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.

• Authors: Christine E MacBrayne, Kristen M Marks, Daniel S Fierer, Susanna Naggie, Raymond T Chung, Michael D Hughes, Arthur Y Kim, Marion G Peters, Diana M Brainard, Sharon M Seifert, Jose R Castillo-Mancilla, Lane R Bushman, Peter L Anderson, Jennifer J Kiser
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 73 Issue 8 Pg. 2112-2119 (08 01 2018) ISSN: 1460-2091 [Electronic] England
• PMID: 29746648 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Benzimidazoles
• Fluorenes
• Organophosphates
• ledipasvir, sofosbuvir drug combination
• tenofovir diphosphate
• Ribavirin
• Tenofovir
• Uridine Monophosphate
• Adenine
• Sofosbuvir

Topics

• Adenine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Adult
• Antiviral Agents (therapeutic use)
• Benzimidazoles
• Coinfection (drug therapy)
• Drug Interactions
• Fluorenes
• HIV Infections (drug therapy)
• Hepatitis C (drug therapy)
• Humans
• Male
• Middle Aged
• Organophosphates (pharmacokinetics, therapeutic use)
• Ribavirin (therapeutic use)
• Sofosbuvir (therapeutic use)
• Tenofovir (pharmacokinetics, therapeutic use)
• Uridine Monophosphate (analogs & derivatives)