Australian Commentary to the US DHHS Guidelines for the use of Antiretroviral Agents in Adults and Adolescents with HIV

US DHHS Guidelines with Australian Commentary

To visit the Pediatric Antiretroviral Guidelines, visit this link.

ARV Guidelines > Adult Guidelines > Drug-Drug Interactions > Interactions between INSTI & NNRTI or PI

Interactions between Integrase Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors

DHHS Last Updated: June 2021Australian Commentary Last Updated: July 2023

AU Comment: INSTI and NNRTI regimen switches

INSTI metabolism via CYP3A4, concurrent use with inducers results in diminished INSTI plasma concentration – advise caution when switching from NNRTI-based to INSTI-based ART regimens due to NNRTI half-life and resolution of induction effect

AU Comment: Etravirine and cobicistat boosted Integrase regimens

Etravirine (ETR) is not recommended in conjunction with cobicistat-boosted regimens, due to CYP3A4-mediated cobicistat metabolism – expected reduction in cobicistat and thus boosted agent plasma concentration (potential reduction in therapeutic effect, loss of virologic suppression and subsequent development of resistance).

Table 25b. Interactions between Integrase Strand Transfer Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors

Recommendations for managing a particular drug interaction may differ depending on whether a new antiretroviral (ARV) drug is being initiated in a patient on a stable concomitant medication or 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.

Information on drug interactions with oral (PO) cabotegravir (CAB) is not included in this table. The CAB PO tablet is not available in retail pharmacies and will be provided directly to patients for short-term use only (PO lead-in and to bridge intramuscular [IM] administration is delayed).

CAB IM and rilpivirine (RPV) IM also are not included in this table because the combination is a two-drug co-packaged product. Therefore, it is not anticipated that they will be used with oral NNRTIs or PIs.

ARV Drugs by Drug Class		INSTIs
ARV Drugs by Drug Class		BIC	DTG	EVG/c	RAL
NNRTIs
DOR	PK Data	↔ DOR and BIC expected	↔ DOR DTG AUC ↑ 36% and C_min ↑ 27%	↑ DOR expected ↔ EVG	↔ DOR and RAL expected
DOR	Dose	No dose adjustment needed.	No dose adjustment needed.	No dose adjustment needed.	No dose adjustment needed.
EFV	PK Data	↓ BIC expected	With DTG 50 mg Once Daily: DTG AUC ↓ 57% and C_min ↓ 75%	↑ or ↓ EVG, COBI, and EFV possible	With RAL 400 mg Twice Daily: RAL AUC ↓ 36% and C_min ↓ 21% With RAL 1,200 mg Once Daily: ↔ RAL AUC and C_min
EFV	Dose	Do not coadminister.	In Patients Without INSTI Resistance: DTG 50 mg twice daily In Patients With Certain INSTI-Associated Resistance^a or Clinically Suspected INSTI Resistance: Consider alternative combination.	Do not coadminister.	No dose adjustment needed.
ETR	PK Data	↓ BIC expected	ETR 200 mg Twice Daily plus DTG 50 mg Once Daily: DTG AUC ↓ 71% and C_min ↓ 88% ETR 200 mg Twice Daily with (DRV 600 mg plus RTV 100 mg) Twice Daily and DTG 50 mg Once Daily: DTG AUC ↓ 25% and C_min ↓ 37% ETR 200 mg Twice Daily with (LPV 400 mg plus RTV 100 mg) Twice Daily and DTG 50 mg Once Daily: DTG AUC ↑ 11% and C_min ↑ 28%	↑ or ↓ EVG, COBI, and ETR possible	ETR 200 mg Twice Daily plus RAL 400 mg Twice Daily: ETR C_min ↑ 17% RAL C_min ↓ 34%
ETR	Dose	Do not coadminister.	Do not coadminister ETR and DTG without concurrently administering ATV/r, DRV/r, or LPV/r. In Patients Without INSTI Resistance: DTG 50 mg once daily with ETR (concurrently with ATV/r, DRV/r, or LPV/r) In Patients With Certain INSTI-Associated Resistance^a or Clinically Suspected INSTI Resistance: DTG 50 mg twice daily with ETR (concurrently with ATV/r, DRV/r, or LPV/r)	Do not coadminister.	RAL 400 mg twice daily Coadministration with RAL 1,200 mg once daily is not recommended.
NVP	PK Data	↓ BIC expected	With DTG 50 mg Once Daily: DTG AUC ↓ 19% and C_min ↓ 34%	↑ or ↓ EVG, COBI, and NVP possible	No data
NVP	Dose	Do not coadminister.	No dose adjustment needed.	Do not coadminister.	No dose adjustment needed.
RPV	PK Data	No data	With DTG 50 mg Once Daily: ↔ DTG AUC and C_min ↑ 22% ↔ RPV AUC and C_min ↑ 21%	↑ or ↓ EVG, COBI, and RPV PO possible	↔ RPV PO RAL C_min ↑ 27%
RPV	Dose	No dose adjustment needed.	No dose adjustment needed.	Do not coadminister.	No dose adjustment needed.
PIs
ATV	PK Data	ATV 400 mg Once Daily plus BIC 75 mg Single Dose: BIC AUC ↑ 315%	(ATV 400 mg plus DTG 30 mg) Once Daily: DTG AUC ↑ 91% and C_min ↑ 180%	↑ or ↓ EVG, COBI, and ATV possible	With Unboosted ATV: RAL AUC ↑ 72% With Unboosted ATV and RAL 1,200 mg: RAL AUC ↑ 67%
ATV	Dose	Do not coadminister.	No dose adjustment needed.	Do not coadminister.	No dose adjustment needed.
ATV/c	PK Data	BIC AUC ↑ 306%	No data	Not applicable	No data
ATV/c	Dose	Do not coadminister.	No dose adjustment needed.	Do not coadminister two COBI-containing products.	No dose adjustment needed.
ATV/r	PK Data	↑ BIC expected	(ATV 300 mg plus RTV 100 mg) Once Daily plus DTG 30 mg Once Daily: DTG AUC ↑ 62% and C_min ↑ 121%	Not applicable	With (ATV 300 mg plus RTV 100 mg) Once Daily: RAL AUC ↑ 41%
ATV/r	Dose	Do not coadminister.	No dose adjustment needed.	Do not coadminister RTV and COBI.	No dose adjustment needed.
DRV	PK Data	Not applicable	Not applicable	↔ DRV or EVG expected	Not applicable
DRV	Dose	Do not administer DRV without RTV or COBI.	Do not administer DRV without RTV or COBI.	No dose adjustment needed.	Do not administer DRV without RTV or COBI.
DRV/c	PK Data	BIC AUC ↑ 74%	DRV/c plus DTG Once Daily: ↔ DTG, DRV, and COBI DTG 50 mg Once Daily and DRV/r Once Daily Switched to DRV/c: DTG C_min ↑ 100%	Not applicable	No data
DRV/c	Dose	No dose adjustment needed.	No dose adjustment needed.	Do not coadminister two COBI-containing products.	No dose adjustment needed.
DRV/r	PK Data	No data	(DRV 600 mg plus RTV 100 mg) Twice Daily with DTG 30 mg Once Daily: DTG AUC ↓ 22% and C_min ↓ 38%	Not applicable	With (DRV 600 mg plus RTV 100 mg) Twice Daily: RAL AUC ↓ 29% and C_min ↑ 38%
DRV/r	Dose	No dose adjustment needed.	No dose adjustment needed.	Do not coadminister RTV and COBI.	No dose adjustment needed.
LPV/r	PK Data	No data	With (LPV 400 mg plus RTV 100 mg) Twice Daily and DTG 30 mg Once Daily: ↔ DTG	Not applicable	↓ RAL ↔ LPV/r
LPV/r	Dose	Consider alternative combination.	No dose adjustment needed.	Do not coadminister RTV and COBI.	No dose adjustment needed.
^a Refer to DTG product label for details. Key to Symbols: ↑ = increase ↓ = decrease ↔ = no change Key: ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; AUC = area under the curve; BIC = bictegravir; C_min = minimum plasma concentration; CAB = cabotegravir; COBI = cobicistat; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; IM = intramuscular; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PK = pharmacokinetic; PO = oral; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir