Co-administration of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir 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 and ledipasvir/sofosbuvir may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring, if other alternatives are not available. The potential risks and benefits associated with co-administration should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving ledipasvir/sofosbuvir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for adverse reactions related to tenofovir disoproxil fumarate.
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily) with atazanavir/ritonavir (300/100 mg once daily) increased ledipasvir AUC, Cmax and Cmin by 96%, 68% and 118%, respectively. There was no change in the AUC and Cmax of sofosbuvir or GS-331007 (the prominent circulating metabolite of sofosbuvir), but GS-331007 Cmin increased by 42%. Atazanavir AUC and Cmax were unaltered, but Cmin increased by 63%; ritonavir AUC and Cmax were unaltered but Cmin increased by 45%. There was no change in emtricitabine AUC, Cmax and Cmin. Tenofovir AUC was unaltered, but Cmax and Cmin both increased by 47%.
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily) with darunavir/ritonavir (800/100 mg once daily) had no effect on ledipasvir AUC, Cmax or Cmin. Sofosbuvir AUC and Cmax decreased by 27% and 37%, but there was no change in the AUC, Cmax and Cmin of GS-331007 (the prominent circulating metabolite of sofosbuvir). Darunavir AUC, Cmax and Cmin were unaltered; ritonavir AUC and Cmax were unaltered, but Cmin increased by 48%. There was no change emtricitabine AUC, Cmax and Cmin. Tenofovir AUC, Cmax and Cmin increased by 50%, 64% and 59%.
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily) with efavirenz (600 mg once daily) decreased ledipasvir AUC, Cmax and Cmin all by 34%. There was no change in sofosbuvir AUC or Cmax, or in the AUC, Cmax and Cmin of GS-331007 (the prominent circulating metabolite of sofosbuvir). AUC, Cmax and Cmin of efavirenz and emtricitabine were unaltered. Tenofovir AUC, Cmax and Cmin increased by 98%, 79% and 163%.
Coadministration of ledipasvir/sofosbuvir (90/400 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, Cmax and Cmin of ledipasvir, sofosbuvir, GS-331007 (the prominent circulating metabolite of sofosbuvir), emtricitabine or rilpivirine. Tenofovir AUC increased by 40%, Cmax was unaltered and Cmin increased by 91%.
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily) with dolutegravir (50 mg once daily) had no effect on the AUC, Cmax and Cmin of ledipasvir, sofosbuvir, GS-331007 (the prominent circulating metabolite of sofosbuvir), emtricitabine or dolutegravir. Tenofovir AUC, Cmax and Cmin increased by 65%, 61% and 115%, respectively.

Coadministration increases tenofovir concentrations. Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and tenofovir-DF (300 mg once daily) in the presence of atazanavir/ritonavir increased tenofovir Cmax, AUC and Cmin by 47%, 35% and 47%, respectively (n=24). 
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and tenofovir-DF (300 mg once daily) in the presence of darunavir/ritonavir increased tenofovir Cmax, AUC and Cmin by 64%, 50% and 59%, respectively (n=23).
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and tenofovir-DF (300 mg once daily) in the presence of efavirenz increased tenofovir Cmax, AUC and Cmin by 79%, 98% and 163%, respectively (n=15).
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and tenofovir-DF (300 mg once daily) in the presence of rilpivirine increased tenofovir Cmax, AUC and Cmin by 32%, 40% and 91%, respectively (n=14).
Coadministration of ledipasvir/sofosbuvir (90/400 mg once daily) and  tenofovir-DF (300 mg once daily) in the presence of dolutegravir increased tenofovir Cmax, AUC and Cmin by 61%, 65% and 115%, respectively (n=29).
Monitor patients receiving Truvada concomitantly with Harvoni (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF. In patients receiving Truvada concomitantly with Harvoni and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with TDF.