Updated
Reviewed
Jun. 03, 2021

Drug-Drug Interactions

Table 24c. 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-antiretroviral (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.

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

Concomitant Drug NRTI Effect on NRTI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Antimycobacterials
Rifabutin TAF ↓ TAF possible Do not coadminister unless benefits outweigh risks. If coadministered, monitor for virologic response
TDF ↔ AUC TFV No dose adjustment needed.
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 than when TDF is administered alone, but clinical outcomes have not been studied. If coadministered, monitor virologic response.
TDF ↔ AUC TFV No dose adjustment needed.
Rifapentine TAF ↓ TAF possible Do not coadminister unless benefits outweigh risks. If coadministered, monitor for virologic response.
TDF ↔ AUC TFV No dose adjustment needed.
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.
Hormonal Therapies
17-b-estradiol FTC FTC AUC ↓ 14% to 24% No dose adjustment needed.
TDF TFV AUC ↓ 12% to 27% No dose adjustment needed.
Other hormones used for contraception, gender affirming therapy, or menopausal replacement therapy All NRTIs No change expected. No dose adjustment needed.
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 35% to 98% when TDF is given with various PIs and NNRTIs.

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

Further ↑ TFV AUC and Cmax possible when TDF, ledipasvir/sofosbuvir, and PIs are coadministered.

Do not coadminister with EVG/c, TDF, or FTC.

If TDF is used, 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.
Sofosbuvir/Velpatasvir TAF ↔ TFV expected No dose adjustment needed.
TDF TFV Cmax ↑ 44% to 46% and AUC ↑ 40% 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 ↑ 48% and AUC ↑ 39% 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 ↔ 3TC, TDF, and buprenorphine No dose adjustment needed.
TAF ↔ TAF expected No dose adjustment needed.
Methadone ABC Methadone clearance ↑ 22% No dose adjustment needed.
Other drugs
Anticonvulsants Carbamazepine, oxcarbazepine, phenobarbital, phenytoin TAF With Carbamazepine:
  • TAF AUC ↓ 55%
↓ TAF possible with other anticonvulsants		 Do not coadminister.
Riociguat ABC Riociguat AUC ↑ 200% If coadministered, initiate riociguat at 0.5 mg three times daily and monitor for riociguat-related adverse effects (e.g., hypotension).
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.
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.
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; ZDV = zidovudine

Drug-Drug Interactions

Table 24c. 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-antiretroviral (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.

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

Concomitant Drug NRTI Effect on NRTI and/or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Antimycobacterials
Rifabutin TAF ↓ TAF possible Do not coadminister unless benefits outweigh risks. If coadministered, monitor for virologic response
TDF ↔ AUC TFV No dose adjustment needed.
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 than when TDF is administered alone, but clinical outcomes have not been studied. If coadministered, monitor virologic response.
TDF ↔ AUC TFV No dose adjustment needed.
Rifapentine TAF ↓ TAF possible Do not coadminister unless benefits outweigh risks. If coadministered, monitor for virologic response.
TDF ↔ AUC TFV No dose adjustment needed.
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.
Hormonal Therapies
17-b-estradiol FTC FTC AUC ↓ 14% to 24% No dose adjustment needed.
TDF TFV AUC ↓ 12% to 27% No dose adjustment needed.
Other hormones used for contraception, gender affirming therapy, or menopausal replacement therapy All NRTIs No change expected. No dose adjustment needed.
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 35% to 98% when TDF is given with various PIs and NNRTIs.

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

Further ↑ TFV AUC and Cmax possible when TDF, ledipasvir/sofosbuvir, and PIs are coadministered.

Do not coadminister with EVG/c, TDF, or FTC.

If TDF is used, 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.
Sofosbuvir/Velpatasvir TAF ↔ TFV expected No dose adjustment needed.
TDF TFV Cmax ↑ 44% to 46% and AUC ↑ 40% 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 ↑ 48% and AUC ↑ 39% 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 ↔ 3TC, TDF, and buprenorphine No dose adjustment needed.
TAF ↔ TAF expected No dose adjustment needed.
Methadone ABC Methadone clearance ↑ 22% No dose adjustment needed.
Other drugs
Anticonvulsants Carbamazepine, oxcarbazepine, phenobarbital, phenytoin TAF With Carbamazepine:
  • TAF AUC ↓ 55%
↓ TAF possible with other anticonvulsants		 Do not coadminister.
Riociguat ABC Riociguat AUC ↑ 200% If coadministered, initiate riociguat at 0.5 mg three times daily and monitor for riociguat-related adverse effects (e.g., hypotension).
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.
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.
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; ZDV = zidovudine

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