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

• TDF with a boosted protease inhibitor (Drug), also known as Viread or Truvada 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 (Drug), also known as Descovy 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 (Drug), also known as Descovy with a boosted protease inhibitor and Harvoni: 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

Primary outcomes

• 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 [12 weeks and 24 weeks 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)
• Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks [12 weeks, and 24 weeks 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).

Secondary outcomes

• Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS) [12 weeks and 24 and 28 weeks]: 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)
• Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR [12 weeks, 24 weeks, and 28 weeks]: Change in estimated glomerular filtration rate (eGFR)
• Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR [12 weeks, 24 weeks, and 28 weeks]: Change in estimated glomerular filtration rate (eGFR) and renal biomarkers: Urine protein to creatinine ratio (UPCR)
• Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio [12 weeks, 24 weeks, and 28 weeks]: Change in renal biomarkers: urinary beta-2 microglobulin (B2M)/creatinine (Cr) ratio, and urinary retinol binding protein (RBP)/Cr ratio

Sex: All, ages: 18 Years to 70 Years

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

Participant flow

Outcome results

• 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 (Primary), Geometric mean, ng*h/mL: TDF With a Boosted PI 3466 +/- 51.4; TAF With a Boosted PI 743 +/- 35.8; TAF With a Boosted PI and LDV/SOF 868 +/- 40.8
• Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks (Primary), Geometric mean, fmol/10^6 cells: TDF With a Boosted PI 83.0 +/- 66.6; TAF With a Boosted PI 926 +/- 23.4; TAF With a Boosted PI and LDV/SOF 1129 +/- 34.9
• Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS) (Secondary), Geometric mean, fmol/2x7mm punches: TDF With a Boosted PI 36014 +/- 46.4; TAF With a Boosted PI 6735 +/- 45.0; TAF With a Boosted PI and LDV/SOF 6100 +/- 41.0
• Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR (Secondary), Geometric mean, mL/min/1.73 m^2: TDF With a Boosted PI 86.7 +/- 27.6; TAF With a Boosted PI 91.0 +/- 23.0; TAF With a Boosted PI and LDV/SOF 88.1 +/- 24.9
• Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR (Secondary), Geometric mean, mg/g: TDF With a Boosted PI 134 +/- 65.7; TAF With a Boosted PI 118 +/- 50.2; TAF With a Boosted PI and LDV/SOF 97.3 +/- 41.0
• Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio (Secondary), Geometric mean, ug/g: TDF With a Boosted PI 419 +/- 176; TAF With a Boosted PI 224 +/- 167; TAF With a Boosted PI and LDV/SOF 178 +/- 156

Adverse events

Time frame: 40 weeks

Other adverse events by term

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• Study Protocol and Statistical Analysis Plan (PDF, 2018-03-29)

• Jennifer J Kiser, PharmD, Principal investigator, University of Colorado, Denver