The co-administration of didanosine and tenofovir disoproxil fumarate is not recommended. Co-administration of didanosine and tenofovir disoproxil fumarate results in a 40-60% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse events. Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported. A reduced didanosine dose (250 mg) has been tested to avoid over-exposure to didanosine in case of co-administration with tenofovir disoproxil fumarate, but this has been associated with reports of high rate of virological failure and of emergence of resistance at early stage within several tested combinations. Co-administration of didanosine and tenofovir disoproxil fumarate is therefore not recommended, especially in patients with high viral load and low CD4 cell count. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. If this combination is judged strictly necessary, patients should be carefully monitored for efficacy and didanosine related adverse events.
Triple NRTI Therapy:
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when didanosine was combined with tenofovir disoproxil fumarate and lamivudine as a once daily regimen.
Videx Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2016.

Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. Didanosine should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg daily. A dose reduction of didanosine taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended. Administer didanosine 250 mg once daily to adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min and didanosine 200 mg once daily to adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min. The appropriate dose of didanosine coadministered with tenofovir disoproxil fumarate in patients with creatinine clearance of less than 60 mL/min has not been established. Patients should be monitored for didanosine-associated toxicities and clinical response.
Coadministration of tenofovir (300 mg once daily with a light meal) and didanosine (400 mg single dose, 2 h before tenofovir) was studied in 26 HIV-negative subjects. AUC and Cmax of ddI both increased by 48%. Data from 25 subjects showed no change in the AUC and Cmax of tenofovir.
Coadministration of tenofovir (300 mg once daily) and didanosine (400 mg single dose) together and with a light meal was studied in 25 HIV-negative subjects. AUC and Cmax of ddI increased by 60% and 64% respectively. There was no change in the AUC and Cmax of tenofovir.
Coadministration of tenofovir (300 mg once daily) and didanosine (200 mg single dose) together and with a light meal was studied in 33 HIV-negative subjects. When compared to didanosine pharmacokinetics obtained with ddI 250 mg given alone under fasting conditions, AUC of ddI increased by 16% and Cmax decreased by 12%.
Coadministration of tenofovir (300 mg once daily) and didanosine (250 mg single dose) together and with a light meal was studied in 33 HIV-negative subjects. When compared to didanosine pharmacokinetics obtained with ddI 400 mg given alone under fasting conditions, there was no change in the AUC of ddI and a 20% decrease in Cmax.
Coadministration of tenofovir (300 mg once daily) and didanosine (325 mg single dose) together and with a light meal was studied in 33 HIV-negative subjects. When compared to didanosine pharmacokinetics obtained with ddI 400 mg given alone under fasting conditions, AUC of ddI increased by 13% and Cmax decreased by 11%.
Videx Prescribing Information, Bristol-Myers Squibb Company, December 2018.

Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended. Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse events. Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.
Triple NRTI Therapy:
There have been reports of a high rate of virological failure and of emergence of resistance at early stage when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.
Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

Coadministration of tenofovir-DF and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When administered with tenofovir-DF, Cmax and AUC of didanosine increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir-DF with didanosine 400 mg daily. In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with tenofovir-DF. In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with tenofovir-DF. When coadministered, tenofovir-DF and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). For additional information on coadministration of tenofovir-DF and didanosine, please refer to the full prescribing information for didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir-DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. Coadministration of tenofovir-DF (300 mg once daily) and buffered didanosine (250 or 400 mg once daily for 7 days, n=14) had no effect on tenofovir pharmacokinetic parameters. Coadministration of tenofovir-DF (300 mg once daily) and enteric-coated didanosine (250 mg simultaneously with tenofovir-DF and a light meal) decreased didanosine Cmax by 20% and had no effect on AUC when compared to values obtained with didanosine (400 mg) given alone under fasting conditions.
Viread Prescribing Information, Gilead Sciences International Inc, February 2016.

Intracellular concentrations of active phosphate metabolites were determined in three groups of HIV-infected subjects receiving didanosine alone (400 mg once daily, n=16), tenofovir (300 mg once daily, n=8) or didanosine/tenofovir (250/300 mg once daily, n =14). There were no significant differences in ddA-TP or TDF-DP when didanosine or tenofovir were administered alone or in combination. This study does not support the existence of a strong intracellular interaction between didanosine and tenofovir, but can not conclude that there is absolutely no interaction due to small sample size. As ddA-TP concentrations were similar when didanosine given alone (400 mg) or at a reduced dose (250 mg) with tenofovir, the study supports the dose adaptation proposed for this combination.
Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients. Pruvost A, et al. Antimicrob Agents Chemother, 2005, 49: 1907-1914.