Updated
Reviewed
Dec. 18, 2019

Drug-Drug Interactions

Drug Interactions between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents)

Table 21c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents)

This table provides information on the known or predicted interactions between NRTIs and non-ARV drugs. Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. In cases where an interacting drug needs to be replaced with an alternative, providers should exercise their clinical judgement to select the most appropriate alternative medication to use.

Note: Interactions associated with ddI and d4T are not included in this table. Please refer to the FDA product labels for ddI and d4T for information regarding drug interactions between these NRTIs and other drugs.

Table 21c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs
Concomitant Drug NRTI Effect on NRTI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Cytomegalovirus and Hepatitis B Antivirals
Adefovir TAF, TDF No data Do not coadminister. Serum concentrations of TDF and/or other renally eliminated drugs may increase.
Ganciclovir, Valganciclovir TAF, TDF No data Serum concentrations of ganciclovir and/or TFV may increase. Monitor for dose-related toxicities.
ZDV ↔ ZDV expected

↔ ganciclovir expected		 If coadministered, closely monitor for hematologic toxicities.
Hepatitis C Antiviral Agents
Glecaprevir/ Pibrentasvir TAF ↔ TFV AUC No dose adjustment needed.
TDF TFV AUC ↑ 29% No dose adjustment needed.
Ledipasvir/ Sofosbuvir TAF TFV AUC ↑ 27% No dose adjustment needed.
TDF Ledipasvir ↑ TFV AUC 40% to 98% when TDF is given with RPV and EFV

Ledipasvir ↑ TFV Cmin 55% to 80% when TDF is given with various PIs, NNRTIs, or INSTIs

Further ↑ TFV AUC and Cmax possible when TDF is given with PIs		 Do not coadminister with EVG/c/TDF/FTC.

If TDF is used in these patients, monitor for TDF toxicities.

Consider using TAF in patients at risk of TDF-associated adverse events.

Consider using TAF or alternative HCV therapy in patients on TDF plus a PI/r or PI/c. The safety of increased TFV exposure with this combination has not been established.
Ribavirin TDF Ribavirin With Sofosbuvir 400 mg:
  • ↔ TFV AUC
 No dose adjustment needed.
ZDV Ribavirin inhibits phosphorylation of ZDV Consider alternative. If coadministered, closely monitor HIV virologic response and monitor for possible hematologic toxicities.
Sofosbuvir/ Velpatasvir TAF ↔ TAF expected No dose adjustment needed.
TDF TFV Cmax and AUC ↑ 39% to 81% when coadministered with various ARV combinations If TDF is used in these patients, monitor for TDF-related toxicities.

Consider using TAF in patients at risk of TDF-related adverse events.
Sofosbuvir/ Velpatasvir/ Voxilaprevir TAF ↔ TAF expected No dose adjustment needed.
TDF TFV Cmax and AUC ↑ 35% to 55% when coadministered with various ARV combinations If TDF is used in these patients, monitor for TDF-related toxicities.

Consider using TAF in patients at risk of TDF-related adverse events.
INSTIs
DTG TAF ↔ TAF AUC No dose adjustment needed.
TDF ↔ TDF AUC

↔ DTG AUC		 No dose adjustment needed.
RAL TDF RAL AUC ↑ 49% No dose adjustment needed.
Narcotics and Treatment for Opioid Dependence
Buprenorphine 3TC, TDF, ZDV ↔ 3TC, TDF, ZDV, and buprenorphine No dose adjustment needed.
TAF ↔ TAF expected No dose adjustment needed.
Methadone ABC Methadone clearance ↑ 22% No dose adjustment needed.
ZDV ZDV AUC ↑ 29% to 43% Monitor for ZDV-related adverse effects.
Other
Anticonvulsants
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin		 TAF With Carbamazepine:
  • TAF AUC ↓ 55%

↓ TAF possible with other anticonvulsants		 Do not coadminister.
Antimycobacterial
Rifampin		 TAF TAF with Rifampin Compared with TDF Alone:
  • TFV-DP AUC ↑ 4.2-fold
TAF with Rifampin Compared with TAF Alone:
  • TAF AUC ↓ 55%
  • TFV-DP AUC ↓ 36%
TAF 25 mg Twice Daily with Rifampin Compared with TAF Once Daily Alone:
  • TAF AUC ↓ 14%
  • TFV-DP AUC ↓ 24%
 Do not coadminister, unless benefits outweigh risks.

Intracellular TFV-DP levels are higher when TAF is coadministered with rifampin compared to TDF administered alone, but clinical outcomes have not been studied. If coadministered, monitor virologic response.
TDF ↔ AUC TFV No dose adjustment needed.
Atovaquone ZDV ZDV AUC ↑ 31% Monitor for ZDV-related adverse effects.
Rifabutin, Rifapentine TAF ↓ TAF possible Do not coadminister.
St. John’s Wort TAF ↓ TAF possible Do not coadminister.
PIs for Treatment of HIV
ATV (Unboosted), ATV/c, ATV/r TAF TAF 10 mg with ATV/r:
  • TAF AUC ↑ 91%
TAF 10 mg with ATV/c:
  • TAF AUC ↑ 75%
 No dose adjustment needed (use TAF 25 mg).
TDF With ATV (Unboosted):
  • ATV AUC ↓ 25% and Cmin ↓ 23% to 40% (higher Cmin with RTV than without RTV)

TFV AUC ↑ 24% to 37%		 Do not coadminister unboosted ATV with TDF.

Use ATV 300 mg daily plus (RTV 100 mg or COBI 150 mg) daily when coadministering TDF 300 mg daily.

If using TDF and an H2 receptor antagonist in an ART-experienced patient, use ATV 400 mg daily plus (RTV 100 mg or COBI 150 mg) daily.

Monitor for TDF-associated toxicities.
ZDV With ATV (Unboosted):
  • ZDV Cmin ↓ 30% and ↔ ZDV AUC
 Clinical significance unknown. If coadministered, monitor virologic response.
DRV/c TAF TAF 25 mg with DRV/c:
  • ↔ TAF
 No dose adjustment needed.
TDF ↑ TFV possible Monitor for TDF-associated toxicities.
DRV/r TAF TAF 10 mg with DRV/r:
  • ↔ TAF AUC
 No dose adjustment needed.
TDF TFV AUC ↑ 22% and Cmin ↑ 37% Clinical significance unknown. If coadministered, monitor for TDF-associated toxicities.
LPV/r TAF TAF 10 mg with DRV/r:
  • TAF AUC ↑ 47%
 No dose adjustment needed.
TDF ↔ LPV/r AUC

TFV AUC ↑ 32%		 Clinical significance unknown. If coadministered, monitor for TDF-associated toxicities.
TPV/r ABC ABC AUC ↓ 35% to 44% Clinical significance unknown. If coadministered, monitor virologic response.
TAF ↓ TAF expected Do not coadminister, unless benefits outweigh risks.
TDF ↔ TDF AUC

TPV AUC ↓ 9% to 18% and Cmin ↓ 12% to 21%		 No dose adjustment needed.
ZDV ZDV AUC ↓ 31% to 42%

↔ TPV AUC		 Clinical significance unknown. If coadministered, monitor virologic response.
Key to Symbols:
↑ = increase
↓ = decrease
↔ = no change

Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; Cmin = minimum plasma concentration; COBI = cobicistat; d4T = stavudine; ddI = didanosine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG/c = elvitegravir/cobicistat; FDA = Food and Drug Administration; FTC = emtricitabine; HCV = hepatitis C virus; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir; TFV-DP = tenofovir diphosphate; TPV/r = tipranavir/ritonavir; ZDV = zidovudine

Drug-Drug Interactions

Drug Interactions between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents)

Table 21c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs (Including Antiretroviral Agents)

This table provides information on the known or predicted interactions between NRTIs and non-ARV drugs. Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. In cases where an interacting drug needs to be replaced with an alternative, providers should exercise their clinical judgement to select the most appropriate alternative medication to use.

Note: Interactions associated with ddI and d4T are not included in this table. Please refer to the FDA product labels for ddI and d4T for information regarding drug interactions between these NRTIs and other drugs.

Table 21c. Drug Interactions Between Nucleoside Reverse Transcriptase Inhibitors and Other Drugs
Concomitant Drug NRTI Effect on NRTI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Cytomegalovirus and Hepatitis B Antivirals
Adefovir TAF, TDF No data Do not coadminister. Serum concentrations of TDF and/or other renally eliminated drugs may increase.
Ganciclovir, Valganciclovir TAF, TDF No data Serum concentrations of ganciclovir and/or TFV may increase. Monitor for dose-related toxicities.
ZDV ↔ ZDV expected

↔ ganciclovir expected		 If coadministered, closely monitor for hematologic toxicities.
Hepatitis C Antiviral Agents
Glecaprevir/ Pibrentasvir TAF ↔ TFV AUC No dose adjustment needed.
TDF TFV AUC ↑ 29% No dose adjustment needed.
Ledipasvir/ Sofosbuvir TAF TFV AUC ↑ 27% No dose adjustment needed.
TDF Ledipasvir ↑ TFV AUC 40% to 98% when TDF is given with RPV and EFV

Ledipasvir ↑ TFV Cmin 55% to 80% when TDF is given with various PIs, NNRTIs, or INSTIs

Further ↑ TFV AUC and Cmax possible when TDF is given with PIs		 Do not coadminister with EVG/c/TDF/FTC.

If TDF is used in these patients, monitor for TDF toxicities.

Consider using TAF in patients at risk of TDF-associated adverse events.

Consider using TAF or alternative HCV therapy in patients on TDF plus a PI/r or PI/c. The safety of increased TFV exposure with this combination has not been established.
Ribavirin TDF Ribavirin With Sofosbuvir 400 mg:
  • ↔ TFV AUC
 No dose adjustment needed.
ZDV Ribavirin inhibits phosphorylation of ZDV Consider alternative. If coadministered, closely monitor HIV virologic response and monitor for possible hematologic toxicities.
Sofosbuvir/ Velpatasvir TAF ↔ TAF expected No dose adjustment needed.
TDF TFV Cmax and AUC ↑ 39% to 81% when coadministered with various ARV combinations If TDF is used in these patients, monitor for TDF-related toxicities.

Consider using TAF in patients at risk of TDF-related adverse events.
Sofosbuvir/ Velpatasvir/ Voxilaprevir TAF ↔ TAF expected No dose adjustment needed.
TDF TFV Cmax and AUC ↑ 35% to 55% when coadministered with various ARV combinations If TDF is used in these patients, monitor for TDF-related toxicities.

Consider using TAF in patients at risk of TDF-related adverse events.
INSTIs
DTG TAF ↔ TAF AUC No dose adjustment needed.
TDF ↔ TDF AUC

↔ DTG AUC		 No dose adjustment needed.
RAL TDF RAL AUC ↑ 49% No dose adjustment needed.
Narcotics and Treatment for Opioid Dependence
Buprenorphine 3TC, TDF, ZDV ↔ 3TC, TDF, ZDV, and buprenorphine No dose adjustment needed.
TAF ↔ TAF expected No dose adjustment needed.
Methadone ABC Methadone clearance ↑ 22% No dose adjustment needed.
ZDV ZDV AUC ↑ 29% to 43% Monitor for ZDV-related adverse effects.
Other
Anticonvulsants
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin		 TAF With Carbamazepine:
  • TAF AUC ↓ 55%

↓ TAF possible with other anticonvulsants		 Do not coadminister.
Antimycobacterial
Rifampin		 TAF TAF with Rifampin Compared with TDF Alone:
  • TFV-DP AUC ↑ 4.2-fold
TAF with Rifampin Compared with TAF Alone:
  • TAF AUC ↓ 55%
  • TFV-DP AUC ↓ 36%
TAF 25 mg Twice Daily with Rifampin Compared with TAF Once Daily Alone:
  • TAF AUC ↓ 14%
  • TFV-DP AUC ↓ 24%
 Do not coadminister, unless benefits outweigh risks.

Intracellular TFV-DP levels are higher when TAF is coadministered with rifampin compared to TDF administered alone, but clinical outcomes have not been studied. If coadministered, monitor virologic response.
TDF ↔ AUC TFV No dose adjustment needed.
Atovaquone ZDV ZDV AUC ↑ 31% Monitor for ZDV-related adverse effects.
Rifabutin, Rifapentine TAF ↓ TAF possible Do not coadminister.
St. John’s Wort TAF ↓ TAF possible Do not coadminister.
PIs for Treatment of HIV
ATV (Unboosted), ATV/c, ATV/r TAF TAF 10 mg with ATV/r:
  • TAF AUC ↑ 91%
TAF 10 mg with ATV/c:
  • TAF AUC ↑ 75%
 No dose adjustment needed (use TAF 25 mg).
TDF With ATV (Unboosted):
  • ATV AUC ↓ 25% and Cmin ↓ 23% to 40% (higher Cmin with RTV than without RTV)

TFV AUC ↑ 24% to 37%		 Do not coadminister unboosted ATV with TDF.

Use ATV 300 mg daily plus (RTV 100 mg or COBI 150 mg) daily when coadministering TDF 300 mg daily.

If using TDF and an H2 receptor antagonist in an ART-experienced patient, use ATV 400 mg daily plus (RTV 100 mg or COBI 150 mg) daily.

Monitor for TDF-associated toxicities.
ZDV With ATV (Unboosted):
  • ZDV Cmin ↓ 30% and ↔ ZDV AUC
 Clinical significance unknown. If coadministered, monitor virologic response.
DRV/c TAF TAF 25 mg with DRV/c:
  • ↔ TAF
 No dose adjustment needed.
TDF ↑ TFV possible Monitor for TDF-associated toxicities.
DRV/r TAF TAF 10 mg with DRV/r:
  • ↔ TAF AUC
 No dose adjustment needed.
TDF TFV AUC ↑ 22% and Cmin ↑ 37% Clinical significance unknown. If coadministered, monitor for TDF-associated toxicities.
LPV/r TAF TAF 10 mg with DRV/r:
  • TAF AUC ↑ 47%
 No dose adjustment needed.
TDF ↔ LPV/r AUC

TFV AUC ↑ 32%		 Clinical significance unknown. If coadministered, monitor for TDF-associated toxicities.
TPV/r ABC ABC AUC ↓ 35% to 44% Clinical significance unknown. If coadministered, monitor virologic response.
TAF ↓ TAF expected Do not coadminister, unless benefits outweigh risks.
TDF ↔ TDF AUC

TPV AUC ↓ 9% to 18% and Cmin ↓ 12% to 21%		 No dose adjustment needed.
ZDV ZDV AUC ↓ 31% to 42%

↔ TPV AUC		 Clinical significance unknown. If coadministered, monitor virologic response.
Key to Symbols:
↑ = increase
↓ = decrease
↔ = no change

Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; Cmin = minimum plasma concentration; COBI = cobicistat; d4T = stavudine; ddI = didanosine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG/c = elvitegravir/cobicistat; FDA = Food and Drug Administration; FTC = emtricitabine; HCV = hepatitis C virus; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PI/c = protease inhibitor/cobicistat; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir; TFV-DP = tenofovir diphosphate; TPV/r = tipranavir/ritonavir; ZDV = zidovudine
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