Co-administration of tenofovir disoproxil fumarate with sofosbuvir/velpatasvir has been shown to increase plasma concentrations of tenofovir, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). Increased plasma concentrations of tenofovir resulting from co-administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir and may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring. The potential risks and benefits associated with co-administration should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving sofosbuvir/velpatasvir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil fumarate. Concomitant administration of sofosbuvir/velpatasvir and efavirenz is expected to decrease plasma concentrations of velpatasvir. Co-administration of sofosbuvir/velpatasvir with efavirenz-containing regimens is not recommended.
Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily with atazanavir/ritonavir (400/100 mg once daily) had no effect on the AUC and Cmax sofosbuvir or GS-331007 (the prominent circulating metabolite of sofosbuvir), but increased GS-331007 Cmin by 42%. Velpatasvir AUC, Cmax and Cmin increased by 142%, 55% and 301%, respectively. There was no change in atazanavir AUC and Cmax, but Cmin increased by 39%; ritonavir AUC and Cmax were unaltered, but Cmin increased by 29%. Emtricitabine AUC, Cmax and Cmin were unaltered. There was no change in tenofovir AUC, but Cmax and Cmin increased by 55% and 39%.
Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily with darunavir/ritonavir (800/100 mg once daily) decreased sofosbuvir AUC and Cmax by 28% and 38%, but had no effect on AUC, Cmax and Cmin of GS-331007 (the prominent circulating metabolite of sofosbuvir). Velpatasvir AUC and Cmin were unaltered but Cmax decreased by 24%. There was no change in the AUC, Cmax and Cmin of darunavir, ritonavir or emtricitabine. Tenofovir AUC, Cmax and Cmin increased by 39%, 55% and 52%, respectively.
Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily with lopinavir/ritonavir (800/200 mg once daily) decreased sofosbuvir AUC and Cmax by 29% and 41%, but had no effect on AUC, Cmax and Cmin of GS-331007 (the prominent circulating metabolite of sofosbuvir). Velpatasvir AUC was unaltered, Cmax decreased by 30% and Cmin increased by 63%. There was no change in the AUC, Cmax and Cmin of lopinavir, ritonavir or emtricitabine. Tenofovir AUC and Cmin were unaltered, but Cmax increased by 42%.
Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily with raltegravir (400 mg twice daily) had no effect on the AUC and Cmax of sofosbuvir or on the AUC, Cmax and Cmin of GS-331007 (the prominent circulating metabolite of sofosbuvir) and velpatasvir. Raltegravir AUC and Cmax were unaltered, but Cmin decreased by 21%.There was no change in the AUC, Cmax and Cmin emtricitabine. Tenofovir AUC, Cmax and Cmin increased by 40%, 46% and 70%.
Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily with efavirenz (600 mg once daily) had no effect on sofosbuvir AUC but increased Cmax by 38%. There was no effect on AUC, Cmax and Cmin of GS-331007 (the prominent circulating metabolite of sofosbuvir). Velpatasvir AUC, Cmax and Cmin decreased by 53%, 47% and 57%. There was no change in the AUC, Cmax and Cmin of efavirenz or emtricitabine. Tenofovir AUC, Cmax and Cmin increased by 81%, 77% and 121%.
Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily with rilpivirine (25 mg once daily) had no effect on the AUC and Cmax of sofosbuvir, or on the AUC, Cmax and Cmin of  GS-331007 (the prominent circulating metabolite of sofosbuvir), velpatasvir, emtricitabine or rilpivirine. Tenofovir AUC, Cmax and Cmin increased by 40%, 44% and 84%.

Coadministration increases tenofovir concentrations. Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and tenofovir-DF (300 mg once daily) in the presence of rilpivirine increased tenofovir Cmax, AUC and Cmin by 44%, 40% and 84%, respectively (n=24). Coadministration of sofosbuvir/velpatasvir (400/100 mg once daily) and tenofovir-DF (300 mg once daily) in the presence of raltegravir increased tenofovir Cmax, AUC and Cmin by 46%, 40% and 70%, respectively (n=30). Monitor patients receiving Truvada concomitantly with Epclusa (sofosbuvir/velpatasvir) for adverse reactions associated with TDF.

Coadministration of sofosbuvir/velpatasvir (400/100 mg, once daily) and emtricitabine/tenofovir-DF (200/300 mg, once daily) with various ARVs (efavirenz, rilpivirine, dolutegravir, raltegravir, elvitegravir/cobicistat, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir) was studied in groups of healthy volunteers in cross-over studies. All primary PK parameters for sofosbuvir (AUC, Cmax, and Cmin) were within predetermined lack of PK alteration boundaries of 70-143% when coadministered and no changes in GS-331007 exposure (AUC) were observed following coadministration with any ARV regimen. Velpatasvir AUC was not altered in the presence of emtricitabine/tenofovir-DF with rilpivirine, dolutegravir, raltegravir, elvitegravir/cobicistat, darunavir/ritonavir or lopinavir/ritonavir, but decreased by ~50% with in the presence of efavirenz and increased by 142% in the presence of atazanavir/ritonavir. Tenofovir PK data for each regimen were not reported, but tenofovir AUCs were ~40% higher when coadministered with sofosbuvir/velpatasvir, except for in the presence of efavirenz where tenofovir AUC was 81% higher. However, the tenofovir AUC in the presence of efavirenz (3920 ng/ml.h) was consistent with that of other tenofovir-DF containing regimens (4140-5330 ng/ml.h). No pharmacokinetic interactions were identified for emtricitabine. The authors hypothesise the likely mechanism for the increase in tenofovir exposure is intestinal inhibition of P-gp and/or BCRP by velpatasvir. No dose reduction is required but monitoring for tenofovir-related renal toxicity is recommended.