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US DHHS Guidelines with Australian Commentary

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Interactions between INSTI & NNRTI or PI

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

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

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

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
BIC
DTG
EVG/c
RAL
NNRTIs
DORPK Data↔ DOR and BIC expected↔ DOR

DTG AUC ↑ 36% and Cmin ↑ 27%		↑ DOR expected

↔ EVG		↔ DOR and RAL expected
DoseNo dose adjustment needed.No dose adjustment needed.No dose adjustment needed.No dose adjustment needed.
EFVPK Data↓ BIC expectedWith DTG 50 mg Once Daily:
  • DTG AUC ↓ 57% and Cmin ↓ 75%
↑ or ↓ EVG, COBI, and EFV possibleWith RAL 400 mg Twice Daily:
  • RAL AUC ↓ 36% and Cmin ↓ 21%
With RAL 1,200 mg Once Daily:

  • ↔ RAL AUC and Cmin
DoseDo not coadminister.In Patients Without INSTI Resistance:
  • DTG 50 mg twice daily
In Patients With Certain INSTI-Associated Resistancea or Clinically Suspected INSTI Resistance:

  • Consider alternative combination.
Do not coadminister.No dose adjustment needed.
ETRPK Data↓ BIC expectedETR 200 mg Twice Daily plus DTG 50 mg Once Daily:
  • DTG AUC ↓ 71% and Cmin ↓ 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 Cmin ↓ 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 Cmin ↑ 28%
↑ or ↓ EVG, COBI, and ETR possibleETR 200 mg Twice Daily plus RAL 400 mg Twice Daily:
  • ETR Cmin ↑ 17%
  • RAL Cmin ↓ 34%
DoseDo 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 Resistancea 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.
NVPPK Data↓ BIC expectedWith DTG 50 mg Once Daily:
  • DTG AUC ↓ 19% and Cmin ↓ 34%
↑ or ↓ EVG, COBI, and NVP possibleNo data
DoseDo not coadminister.No dose adjustment needed.Do not coadminister.No dose adjustment needed.
RPVPK DataNo dataWith DTG 50 mg Once Daily:
  • ↔ DTG AUC and Cmin ↑ 22%
  • ↔ RPV AUC and Cmin ↑ 21%
↑ or ↓ EVG, COBI, and RPV PO possible↔ RPV PO

RAL Cmin ↑ 27%
DoseNo dose adjustment needed.No dose adjustment needed.Do not coadminister.No dose adjustment needed.
PIs
ATVPK DataATV 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 Cmin ↑ 180%
↑ or ↓ EVG, COBI, and ATV possibleWith Unboosted ATV:
  • RAL AUC ↑ 72%
With Unboosted ATV and RAL 1,200 mg:

  • RAL AUC ↑ 67%
DoseDo not coadminister.No dose adjustment needed.Do not coadminister.No dose adjustment needed.
ATV/cPK DataBIC AUC ↑ 306%No dataNot applicableNo data
DoseDo not coadminister.No dose adjustment needed.Do not coadminister two COBI-containing products.No dose adjustment needed.
ATV/rPK Data↑ BIC expected(ATV 300 mg plus RTV 100 mg) Once Daily plus DTG 30 mg Once Daily:
  • DTG AUC ↑ 62% and Cmin ↑ 121%
Not applicableWith (ATV 300 mg plus RTV 100 mg) Once Daily:
  • RAL AUC ↑ 41%
DoseDo not coadminister.No dose adjustment needed.Do not coadminister RTV and COBI.No dose adjustment needed.
DRVPK DataNot applicableNot applicable↔ DRV or EVG expectedNot applicable
DoseDo 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/cPK DataBIC 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 Cmin ↑ 100%
Not applicableNo data
DoseNo dose adjustment needed.No dose adjustment needed.Do not coadminister two COBI-containing products.No dose adjustment needed.
DRV/rPK DataNo data(DRV 600 mg plus RTV 100 mg) Twice Daily with DTG 30 mg Once Daily:
  • DTG AUC ↓ 22% and Cmin ↓ 38%
Not applicableWith (DRV 600 mg plus RTV 100 mg) Twice Daily:
  • RAL AUC ↓ 29% and Cmin ↑ 38%
DoseNo dose adjustment needed.No dose adjustment needed.Do not coadminister RTV and COBI.No dose adjustment needed.
LPV/rPK DataNo dataWith (LPV 400 mg plus RTV 100 mg) Twice Daily and DTG 30 mg Once Daily:
  • ↔ DTG
Not applicable↓ RAL

↔ LPV/r
DoseConsider 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; Cmin = 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

The ARV Guidelines with Australian commentary is administered by ASHM

The Australian Government Department of Health

While the Australian Department of Health provides financial support for the ARV Guidelines, the material contained in this resource should not be taken to represent the views of the Australian Department of Health.

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