Effects of Ledipasvir/Sofosbuvir on the Pharmacokinetics and Renal Safety of Tenofovir Alafenamide (TAF)

Hepatitis C Clinical Trial

Official title:

Effects of Ledipasvir/Sofosbuvir Treatment on the Pharmacokinetics and Renal Safety of Tenofovir Alafenamide (TAF) in Patients With HIV.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03126370
• Other study ID #: 17-0490
• Status: Completed
• Phase: Phase 4
• Start date: January 8, 2018
• Est. completion date: October 1, 2019

Study information

• Verified date: January 2021
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the effect of ledipasvir/sofosbuvir (LDV/SOF) treatment on the pharmacokinetics (PK) and renal safety of tenofovir in the form of tenofovir alafenamide (TAF). Subjects living with human immunodeficiency virus (HIV) who are receiving tenofovir-based antiretroviral therapy (in the form of tenofovir disoproxil fumarate [TDF]), and are also taking a ritonavir- or cobicistat-boosted protease inhibitor will be invited to participate.

The study will consist of five visits: a screening visit, three abbreviated 4-hour pharmacokinetic visits, and one end-of-study follow-up visit.

Subjects will also be asked to use a Wisepill device, which will track medication adherence throughout the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: October 1, 2019
• Est. primary completion date: July 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Between 18-70 years of age

• Have been taking TDF and a ritonavir- or cobicistat-boosted protease inhibitor as part of standard care for treatment of HIV

Exclusion Criteria:

• eGFR < 30 mL/min

• Pregnant or planning pregnancy

• Breastfeeding

• Any medical, social, or mental-health issue(s) that, in the opinion of the investigators, could interfere with study participation or the study outcomes

• Signs or symptoms of decompensated liver disease

• Hepatitis B infection

• Medications that may cause unwanted drug interactions with ledipasvir/sofosbuvir or emtricitabine/tenofovir alafenamide

• Unwillingness or inability to comply with study procedures

• Chronic hepatitis C infection

Related Conditions & MeSH terms

• Coinfection
• Hepatitis C
• HIV Coinfection
• HIV Infections

Intervention

Drug:
• TDF with a boosted protease inhibitor
Participants who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease inhibitor for HIV treatment will continue to take their prescribed treatment for 12 weeks after enrollment. Other: Blood draws for tenofovir PK, renal function assessment
• TAF with a boosted protease inhibitor
Participants will be switched from tenofovir disoproxil fumarate to tenofovir alafenamide 25 mg/emtricitabine 200 mg with a boosted protease inhibitor. Other: Blood draws for tenofovir PK, renal function assessment
• TAF with a boosted protease inhibitor and LDV/SOF
After taking tenofovir alafenamide/emtricitabine for 12 weeks, participants will then start taking ledipasvir 90 mg/sofosbuvir 400 mg (Harvoni) in combination with the tenofovir alafenamide 25 mg/emtricitabine 200 mg (Descovy) and a boosted protease inhibitor for 4 weeks. Subjects will then return to taking tenofovir alafenamide 25 mg/emtricitabine 200 mg (Descovy) and a boosted protease inhibitor for the final 12 weeks. Other: Blood draws for tenofovir PK, renal function assessment

Locations

Country	Name	City	State
United States	University of Colorado Hospital	Aurora	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
University of Colorado, Denver

Country where clinical trial is conducted

United States, 

References & Publications (26)

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Garrison K ea. Drug Interactions between anti-HCV Antivirals Ledipasvir/Sofosbuvir and Integrase Strand Transfer Inhibitor-Based Regimens. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington DC. May 26-28, 2015, abstrac #71

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Havens PL, Kiser JJ, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, Bethel J, Pan CG, Woodhouse LR, Van Loan MD, Liu N, Lujan-Zilbermann J, Baker A, Kapogiannis BG, Gordon CM, Mulligan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 063 Study Team. Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency? Antimicrob Agents Chemother. 2013 Nov;57(11):5619-28. doi: 10.1128/AAC.01096-13. Epub 2013 Sep 3. — View Citation

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Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV. Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr. 2008 Mar 1;47(3):298-303. — View Citation

Kiser JJ, Carten ML, Aquilante CL, Anderson PL, Wolfe P, King TM, Delahunty T, Bushman LR, Fletcher CV. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther. 2008 Feb;83(2):265-72. Epub 2007 Jun 27. — View Citation

Kiser JJ, Fletcher CV, Flynn PM, Cunningham CK, Wilson CM, Kapogiannis BG, Major-Wilson H, Viani RM, Liu NX, Muenz LR, Harris DR, Havens PL; Adolescent Trials Network for HIV/AIDS Interventions. Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection. Antimicrob Agents Chemother. 2008 Feb;52(2):631-7. Epub 2007 Nov 19. — View Citation

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Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, Marks K, Luetkemeyer A, Baden RP, Sax PE, Gane E, Santana-Bagur J, Stamm LM, Yang JC, German P, Dvory-Sobol H, Ni L, Pang PS, McHutchison JG, Stedman CA, Morales-Ramirez JO, Bräu N, Jayaweera D, Colson AE, Tebas P, Wong DK, Dieterich D, Sulkowski M; ION-4 Investigators. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. N Engl J Med. 2015 Aug 20;373(8):705-13. doi: 10.1056/NEJMoa1501315. Epub 2015 Jul 21. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks	Compare plasma tenofovir AUC0-24 between TAF with boosted PI vs. TDF with boosted PI (Phase 2 vs. 1), and between TAF with boosted PI and LDV/SOF vs. TDF with boosted PI (Phase 3 vs. 1)	12 weeks and 24 weeks and 28 weeks
Primary	Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks	Compare tenofovir-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1).	12 weeks, and 24 weeks and 28 weeks
Secondary	Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS)	Compare tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1)	12 weeks and 24 and 28 weeks
Secondary	Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR	Change in estimated glomerular filtration rate (eGFR)	12 weeks, 24 weeks, and 28 weeks
Secondary	Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR	Change in estimated glomerular filtration rate (eGFR) and renal biomarkers: Urine protein to creatinine ratio (UPCR)	12 weeks, 24 weeks, and 28 weeks
Secondary	Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio	Change in renal biomarkers: urinary beta-2 microglobulin (B2M)/creatinine (Cr) ratio, and urinary retinol binding protein (RBP)/Cr ratio	12 weeks, 24 weeks, and 28 weeks