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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03126370
Other study ID # 17-0490
Secondary ID
Status Completed
Phase Phase 4
First received
Last updated
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
Health authority
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

Study Design


Related Conditions & MeSH terms


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)

Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Di Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014 Apr 17;370(16):1483-93. doi: 10.1056/NEJMoa1316366. Epub 2014 Apr 11. — View Citation

Anderson PL, Glidden DV, Bushman LR, Heneine W, García-Lerma JG. Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission. J Antimicrob Chemother. 2014 Sep;69(9):2470-6. doi: 10.1093/jac/dku162. Epub 2014 May 26. — View Citation

Anderson PL, Glidden DV, Liu A, Buchbinder S, Lama JR, Guanira JV, McMahan V, Bushman LR, Casapía M, Montoya-Herrera O, Veloso VG, Mayer KH, Chariyalertsak S, Schechter M, Bekker LG, Kallás EG, Grant RM; iPrEx Study Team. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012 Sep 12;4(151):151ra125. — View Citation

Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, Grant RM. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection. J Antimicrob Chemother. 2011 Feb;66(2):240-50. doi: 10.1093/jac/dkq447. Epub 2010 Nov 30. Review. — View Citation

Bushman LR, Kiser JJ, Rower JE, Klein B, Zheng JH, Ray ML, Anderson PL. Determination of nucleoside analog mono-, di-, and tri-phosphates in cellular matrix by solid phase extraction and ultra-sensitive LC-MS/MS detection. J Pharm Biomed Anal. 2011 Sep 10;56(2):390-401. doi: 10.1016/j.jpba.2011.05.039. Epub 2011 Jun 6. — View Citation

Castillo-Mancilla J, Coyle R, Zheng J, al e. Tenofovir Diphosphate Arising from TAF is Quantifiable in Dried Blood Spots. Conference on Retroviruses and Opportunistic Infections. Seattle Washington, February 13-16, 2017.

Cope R PA, Glowa T, Faulds S, Veldkamp P, Prasad R. Majority of HIV/HCV Co-infected Patients Require Antiretroviral Therapy Switch Prior to Use of Simeprevir (abstract 651). CROI 2015; February 23-26, 2015. Seattle, WA.

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

Genovese D, Boesecke C, Coppola N, Vella S. Virus Variability and Its Impact on HIV and Hepatitis Therapy. Adv Virol. 2012;2012:607527. doi: 10.1155/2012/607527. Epub 2012 Dec 27. — View Citation

German P GK, Pang PS, et al. Drug Interactions Between the anti-HCV Regimen Ledipasvir/Sofosbuvir and Ritonavir-Boosted Protease Inhibitors plus Emtricitabine/Tenofovir DF. CROI 2015; February 23-26, 2015; Seattle WA.

Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis. 2011 May;57(5):773-80. doi: 10.1053/j.ajkd.2011.01.022. Epub 2011 Mar 23. Review. — View Citation

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

Höner Zu Siederdissen C, Maasoumy B, Marra F, Deterding K, Port K, Manns MP, Cornberg M, Back D, Wedemeyer H. Drug-Drug Interactions With Novel All Oral Interferon-Free Antiviral Agents in a Large Real-World Cohort. Clin Infect Dis. 2016 Mar 1;62(5):561-7. doi: 10.1093/cid/civ973. Epub 2015 Nov 26. — View Citation

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

Langness J LB, Rogers M, J. KJ. Readying HIV/HCV Coinfected Patients for HCV Treatment: Occurrence and Management of Antiviral Interactions (abstract 18). 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; May 26-28, 2015; Washington, DC.

MacBrayne CE MK, Fierer DS, et al. Increase Tenofovir Diphosphate in Red Blood Cells, but Not Tenofovir in Plasma, with Sofosbuvir and Ribavirin. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; Washington DC, June 2016 Accepted Abstract (Oral).

MacBrayne CE, Kiser JJ. Pharmacologic Considerations in the Treatment of Hepatitis C Virus in Persons With HIV. Clin Infect Dis. 2016 Jul 15;63 Suppl 1:S12-23. doi: 10.1093/cid/ciw220. Review. Erratum in: Clin Infect Dis. 2016 Sep 1;63(5):715. — View Citation

Monteiro N, Branco M, Peres S, Borges F, Mansinho K. The impact of tenofovir disoproxil fumarate on kidney function: four-year data from the HIV-infected outpatient cohort. J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19565. doi: 10.7448/IAS.17.4.19565. eCollection 2014. — View Citation

Moss DM, Neary M, Owen A. The role of drug transporters in the kidney: lessons from tenofovir. Front Pharmacol. 2014 Nov 11;5:248. doi: 10.3389/fphar.2014.00248. eCollection 2014. Review. Erratum in: Front Pharmacol. 2015;6:18. — View Citation

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

Ruane PJ, DeJesus E, Berger D, Markowitz M, Bredeek UF, Callebaut C, Zhong L, Ramanathan S, Rhee MS, Fordyce MW, Yale K. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013 Aug 1;63(4):449-55. doi: 10.1097/QAI.0b013e3182965d45. — View Citation

Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, Wang H, Callebaut C, Martin H, Fordyce MW, McCallister S. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014 Sep 1;67(1):52-8. doi: 10.1097/QAI.0000000000000225. — View Citation

Sulkowski MS. Hepatitis C virus-human immunodeficiency virus coinfection. Liver Int. 2012 Feb;32 Suppl 1:129-34. doi: 10.1111/j.1478-3231.2011.02719.x. Review. — View Citation

Tourret J, Deray G, Isnard-Bagnis C. Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? J Am Soc Nephrol. 2013 Oct;24(10):1519-27. doi: 10.1681/ASN.2012080857. Epub 2013 Sep 19. Review. — View Citation

* Note: There are 26 references in allClick 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
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