Liverpool HIV Interactions

Do Not Coadminister

Emtricitabine (FTC)

Emtricitabine/Tenofovir alafenamide (FTC/TAF)

Quality of Evidence: Very Low

Summary:

Descovy contains emtricitabine and therefore should not be administered with additional emtricitabine.

Description:

Descovy should not be administered concomitantly with medicinal products containing tenofovir alafenamide or emtricitabine.

Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2022.

Emtricitabine should not be taken with any other medicinal products containing emtricitabine.

Emtriva Summary of Product Characteristics, Gilead Sciences Ltd, April 2019.

Do Not Coadminister

Tenofovir-DF (TDF)

Emtricitabine/Tenofovir alafenamide (FTC/TAF)

Quality of Evidence: Very Low

Summary:

Descovy contains tenofovir alafenamide and therefore should not be administered with tenofovir-DF.

Description:

Descovy should not be administered concomitantly with medicinal products containing tenofovir disoproxil.

Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2022.

Do Not Coadminister

Efavirenz (EFV)

Doravirine (DOR)

Quality of Evidence: Low

Summary:

Doravirine should not be administered with another NNRTI. Furthermore, coadministration is expected to decrease doravirine exposure. Note: switching from efavirenz to doravirine resulted in a transient decrease in doravirine exposure (doravirine AUC, Cmax and Cmin decreased by 52%, 35% and 85%, respectively, one day after stopping efavirenz and by 32%, 14% and 50%, respectively, 14 days after stopping efavirenz). Dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed individual.

Description:

Use with efavirenz is not recommended. Co-administration of efavirenz (600 mg daily) with doravirine (100 mg single dose, given the first day following the cessation of efavirenz) was studied in 17 subjects. Doravirine AUC, Cmax and C24 decreased by 62%, 35% and 85% respectively. Fourteen days following the cessation of efavirenz, doravirine AUC, Cmax and C24 were decreased by 32%, 14% and 50%, respectively.

Pifeltro US Prescribing Information, Merck & Co Inc, August 2018.

No studies have been performed with efavirenz in combination with other NNRTIs. Since use of two NNRTIs proved not beneficial in terms of efficacy and safety, coadministration of efavirenz and another NNRTI is not recommended.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

Combining two NNRTIs has not been shown to be beneficial. Efavirenz should not be coadministered with other NNRTIs.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

The effect of switching from efavirenz (600 mg once daily for 14 days) to doravirine (100 mg, once daily, for 14 days) was studied in 17 healthy subjects. There was no wash-out period between the two drug regimens. Doravirine AUC, Cmax and C24 were decreased by 62%, 35% and 85% respectively, one day after switching. These decreases recovered to 32%, 14%, and 50% for AUC, Cmax, and C24, respectively, by day 14 after efavirenz cessation. Doravirine C24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4 following cessation. The authors conclude that it is safe to switch from efavirenz to doravirine, as at all times drug concentrations were above the minimum required for an antiviral effect.

Evaluation of doravirine pharmacokinetics when switching from efavirenz to doravirine in healthy subjects, Yee KL, Sanchez RI, Auger P, et al. Antimicrob Agents Chemother, 2017, 61(2): e01757-16.

Potential Interaction

Efavirenz (EFV)

Dolutegravir (DTG)

Quality of Evidence: High

Summary:

Coadministration decreases dolutegravir exposure and a dose increase of dolutegravir is recommended. Coadministration of efavirenz (600 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 39%, 57% and 75%, respectively. When compared to historical data, dolutegravir did not appear to affect the pharmacokinetics of efavirenz. In treatment-naïve or INSTI-naïve patients, a dose adjustment of dolutegravir to 50 mg twice daily is recommended. Alternative combinations that do not include metabolic inducers should be considered where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. Switching from efavirenz to dolutegravir decreased dolutegravir Ctrough by 60% and 85% in CYP2B6 normal and slow/intermediate metabolizers, respectively. CYP2B6 slow metabolizers experienced more prolonged subtherapeutic dolutegravir concentrations. When switching from efavirenz to dolutegravir, consider administering dolutegravir 50 mg twice daily for 2 weeks in patients who are not virologically suppressed, or who have resistance to efavirenz, or in patients who are CYP2B6 slow metabolizers.

Description:

Coadministration decreased dolutegravir AUC, Cmax and Ctrough by 57%, 39% and 75%, respectively by induction of UGT1A1 and CYP3A enzymes. The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz. In paediatric patients the weight-based once daily dose should be administered twice daily. In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered.

Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.

Coadministration of efavirenz (600 mg once daily) and dolutegravir (50 mg once daily) to 12 subjects decreased dolutegravir Cmax, AUC and Ctrough by 39%, 57% and 75%, respectively. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of efavirenz. Adjust dose of dolutegravir to 50 mg twice daily for treatment-naïve and treatment experienced, INSTI-naïve patients. In pediatric patients, increase the weight-based dose to twice daily. Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI associated resistance substitutions or clinically suspected INSTI resistance) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to dolutegravir or other coadministered antiretroviral agents.

Tivicay US Prescribing Information, ViiV Healthcare, July 2019.

Coadministration of dolutegravir (50 mg once daily) and efavirenz (600 mg once daily) was studied in 12 HIV-negative subjects. In the presence of efavirenz, dolutegravir AUC, Cmax and Ctrough decreased by 57%, 39%, 75%, respectively (likely via UGT and CYP3A induction by efavirenz). However, dolutegravir concentrations remained 4-5 fold higher than the protein-adjusted IC90 for the wild type virus and the authors concluded no dose adjustment was required when dolutegravir and efavirenz were given concomitantly in integrase naïve patients.

Song I, Borland J, Lou Y et al. 12th International Workshop on Clinical Pharmacology of HIV Therapy, Miami 2011; abstract O_02.

Efavirenz is primarily metabolized by CYP2B6. This study evaluated the effect of CYP2B6 genotype on the pharmacokinetic interaction between efavirenz and dolutegravir. Twelve HIV-negative adults received dolutegravir 50 mg once daily for 5 days (period 1), followed by efavirenz 600 mg + dolutegravir 50 mg once daily for 14 days (period 2). Nine individuals were genotyped for rs3745274 (1/*1, *1/*6 or *6/*6). Dolutegravir Ctrough decreased by 85% in CYP2B6 slow and intermediate metabolizers and by 60% in CYP2B6 normal metabolizers. Efavirenz half-life was 2.7 times higher in CYP2B6 slow (39.1 hours, 95% CI 17.1-89.5 hours) than in normal metabolizers (14.3 hours, 95% CI 12.6-16.1 hours) and was 24.6 hours in the intermediate metabolizers. This study demonstrated a strong association between CYP2B6 slow metabolizer genotype (and resulting increased efavirenz exposure) with plasma dolutegravir concentrations. Switch from efavirenz to dolutegravir is of little concern for individuals with viremia well controlled because at no time both dolutegravir and efavirenz concentrations simultaneously fall below their respective clinical target concentrations. However, switch could be problematic in individuals with uncontrolled viremia and efavirenz resistances in which case efavirenz will not protect dolutegravir during its period of subtherapeutic exposure. The safest strategy would be to switch from efavirenz to dolutegravir when HIV is well suppressed. If HIV replication is not controlled and if resistances to efavirenz are present, prescription of dolutegravir 50 mg twice daily might be considered up to 2 weeks after the switch. The same strategy might be applied to CYP2B6 slow metabolizers.

Implications of efavirenz pharmacogenetics when switching from efavirenz- to dolutegravir-containing antiretroviral regimens. Haas DW, Acosta EP. Clin Infect Dis. 2021; 72(10):1820-1822.

Dolutegravir is the preferred second-line antiretroviral backbone agent for people living with HIV failing a first-line efavirenz-based regimen. Efavirenz induces metabolism and was shown to reduce dolutegravir exposure for up to 14 days when switching from an efavirenz-based regimen. Exposure to sub-therapeutic dolutegravir concentrations in people living with HIV failing efavirenz-based first-line antiretrovirals could select for dolutegravir resistance mutations. This study evaluated dolutegravir trough concentrations after switching from a failing first-line efavirenz-based regimen to assess the need for a lead-in supplemental dose of dolutegravir. Participants failing a first-line efavirenz-based regimen were randomized to receive supplemental dolutegravir 50 mg or placebo for 14 days post-switch to tenofovir/lamivudine/dolutegravir (TLD). Efavirenz was measured at baseline and days 3, 7 and 14 and dolutegravir trough concentrations at days 3, 7, 14 and 28. 36 participants were enrolled: 11 in the placebo arm and 25 in the supplemental arm. One participant in the supplemental dolutegravir arm and none in the placebo arm had a dolutegravir trough concentration below the PA-IC90 (64 ng/mL) at day 3. There were no slow metabolizers in the placebo arm and 5 in the supplemental arm. In summary, no participants in the placebo arm had dolutegravir trough concentrations below the PA-IC90. Prolonged efavirenz induction effect in CYP2B6 slow metabolizers contributed to lower dolutegravir trough concentrations at day 28 in the supplemental arm. This finding does not support the need for a supplemental dolutegravir dose when switching from a failing first-line efavirenz based regimen.

Pharmacokinetics of standard vs double-dose dolutegravir after switch from efavirenz. Griesel R, Banda C, Zhao Y, et al. CROI 2023, Seattle February 19-22, abstract 507.

Potential Interaction

Tenofovir-DF (TDF)

Valaciclovir

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied. Since tenofovir-DF is primarily eliminated by the kidneys, coadministration with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir or the coadministered drug. Tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Description:

Tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. Since tenofovir-DF is primarily eliminated by the kidneys, coadministration of tenofovir-DF with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some example include, but are not limited to cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir.
Viread Prescribing Information, Gilead Sciences International Inc, February 2016.

No Interaction Expected

Emtricitabine (FTC)

Doravirine (DOR)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doravirine is metabolized by CYP3A4. Emtricitabine does not interfere with CYP450 mediated metabolism.

Description:

Co-administration has not been studied but no effect on doravirine or emtricitabine is expected. No dose adjustment is required.

Pifeltro Summary of Product Characteristics, Merck Sharp & Dohme Ltd, November 2018.

No Interaction Expected

Tenofovir-DF (TDF)

Doravirine (DOR)

Quality of Evidence: Low

Summary:

Coadministration has no significant effect on the pharmacokinetics of doravirine or tenofovir. Coadministration of doravirine (100 mg single dose) and tenofovir-DF (300 mg once daily) decreased doravirine AUC, Cmax and C24 by 3%, 18% and 5%, respectively (n=8).

Description:

Co-administration of tenofovir disoproxil (245 mg once daily) and doravirine (100 mg single dose) decreased doravirine AUC, Cmax and C24 by 5%, 20% and 6%, respectively. No dose adjustment is required.

Pifeltro Summary of Product Characteristics, Merck Sharp & Dohme Ltd, November 2018.

No clinically significant changes in either drug concentration were observed when doravirine was co-administered with tenofovir disoproxil fumarate.

Pifeltro US Prescribing Information, Merck & Co Inc, August 2018.

Co-administration of doravirine (100 mg single dose) with tenofovir-DF (300 mg once daily) was studied in 8 healthy male subjects. Doravirine AUC, Cmax and C24 decreased by 3%, 18% and 5%, respectively. The authors conclude that tenofovir-DF does not have not have a clinically relevant impact on doravirine pharmacokinetics.

Effect of ritonavir (RTV) and tenofovir (TDF) on the pharmacokinetics of MK-1439, a novel HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Anderson MS, Gilmartin J, Mitselos A, et al. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, September 2013, abstract: H-1462.

No Interaction Expected

Efavirenz (EFV)

Valaciclovir

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valaciclovir is converted to aciclovir which is eliminated renally via glomerular filtration and active renal secretion by OAT1.

Description:

(See Summary)

No Interaction Expected

Emtricitabine (FTC)

Valaciclovir

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valaciclovir is converted to aciclovir which is eliminated renally via glomerular filtration and active renal secretion by OAT1.

Description:

(See Summary)

No Interaction Expected

Emtricitabine (FTC)

Dolutegravir (DTG)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically relevant drug interaction is unlikely.

Description:

(See Summary)

No Interaction Expected

Tenofovir-DF (TDF)

Dolutegravir (DTG)

Quality of Evidence: Low

Summary:

No clinically significant pharmacokinetic interaction was observed between tenofovir-DF and dolutegravir. Coadministration of tenofovir-DF (300 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax and Ctrough by 3% and 8%, and increased AUC by 1%. Tenofovir Cmax, AUC and Ctrough increased by 9%, 12% and 19%, respectively. No dosage adjustment is necessary.

Description:

Coadministration had no significant effect on dolutegravir exposure (AUC increased by 1%, Cmax and Ctrough decreased by 3% and 8%). There was no effect on tenofovir exposure. No dosage adjustment is necessary.

Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.

Based on drug interaction trial results, tenofovir can be coadministered with dolutegravir without a dose adjustment. Coadministration of tenofovir-DF (300 mg once daily) and dolutegravir (50 mg once daily) was studied in 15 subjects. Dolutegravir Cmax and Ctrough decreased by 3% and 8%, and AUC increased by 1%. Tenofovir Cmax, AUC and Ctrough increased by 9%, 12% and 19%, respectively.

Tivicay US Prescribing Information, ViiV Healthcare, July 2019.

Coadministration of dolutegravir (50 mg once daily) and tenofovir-DF (300 mg once daily) was studied in 15 HIV-negative subjects. The pharmacokinetic parameters of tenofovir and dolutegravir when coadministered were comparable to those when given alone, demonstrating no significant drug interaction. Dolutegravir AUC increased by 1%, but Cmax and Ctrough decreased by 3% and 8%, respectively. Tenofovir AUC, Cmax and Ctrough increased by 12%, 9% and 19%, respectively.

Lack of interaction between the HIV integrase inhibitor S/GSK1349572 and tenofovir in healthy subjects. Song I, Min SS, Borland J, et al. J AIDS, 2010, 55(3): 365-367.

No Interaction Expected

Efavirenz (EFV)

Emtricitabine/Tenofovir alafenamide (FTC/TAF)

Quality of Evidence: Low

Summary:

Coadministration of efavirenz (600 mg once daily) and emtricitabine/tenofovir alafenamide (200/40 mg once daily decreased tenofovir alafenamide AUC and Cmax by 14% and 22%; tenofovir AUC and Cmax decreased by 20% and 24% (n=11). The recommended dose of Descovy for HIV-1 treatment is 200/25 mg once daily.

Description:

When given with efavirenz for HIV-1 treatment, the dose of Descovy is 200/25 mg once daily. Coadministration of efavirenz (600 mg once daily) and tenofovir alafenamide (40 mg once daily, given as Descovy) decreased tenofovir alafenamide AUC and Cmax by 14% and 22%.

Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2022.

Based on drug interaction studies conducted with the components of Descovy, no clinically significant drug interactions have been either observed or are expected when Descovy is combined with efavirenz. Coadministration of efavirenz (600 mg once daily) and tenofovir alafenamide (40 mg once daily, dosed as Descovy) was studied in 11 subjects. Tenofovir alafenamide Cmax and AUC decreased by 22% and 14%.

Descovy US Prescribing Information, Gilead Sciences Inc, January 2022.

Specific interaction studies have not been performed with efavirenz and NRTIs other than lamivudine, zidovudine, and tenofovir disoproxil fumarate. Clinically significant interactions are not expected since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. No dosage adjustment is necessary for either medicinal product.

Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, May 2023.

No dosage adjustment is recommended when efavirenz is given with emtricitabine.

Efavirenz US Prescribing Information, Aurobindo Pharma Limited, October 2021.

Coadministration of efavirenz (600 mg once daily) with emtricitabine/tenofovir alafenamide (200/40 mg once daily) was studied in 11 healthy volunteers in a crossover study. Tenofovir alafenamide AUC and Cmax decreased by 14% and 22%, respectively. Tenofovir AUC and Cmax decreased by 20% and 24%, respectively. Efavirenz pharmacokinetic parameters were similar to historical controls. The authors hypothesise that the decrease in tenofovir alafenamide and tenofovir exposures are due to intestinal induction of P-gp by efavirenz and that this reduction is not clinically relevant, as equivalent tenofovir exposures were associated with efficacy in phase 3 trials.

Pharmacokinetics of tenofovir alafenamide when coadministered with other HIV antiretrovirals. Begley R, Das M, Zhong L, et al. J Acquir Immune Defic Syndr, 2018, 78(4): 465-472.

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