Important drug-drug interactions to consider

In general, watch out for the potent enzyme inducers such as rifampicin, rifabutin, phenytoin and carbamazepine

Specific interactions by ARV drug class to be aware of and their management, where appropriate, include:

INSTIs

  • Dolutegravir with metformin: adjust metformin dose.
  • All INSTIs with cationic chelation (e.g. iron, magnesium, calcium, zinc), including antacids containing these cations: separate drug administration by 2 hours.

NNRTIs

  • Rilpivirine with antacids, proton pump inhibitors and H2 antagonists.
  • Nevirapine, efavirenz and etravirine with midazolam, direct acting anticoagulants, warfarin, antiplatelet agents, some hormonal products and methadone.

PIs and low-dose ritonavir or cobicistat

  • All PIs (to a varying degree) with midazolam, corticosteroids (including by inhalation), some statins, direct acting anticoagulants, warfarin, antiplatelet agents, sildenafil (and other phosphodiesterase inhibitors), some hormonal and chemotherapeutic agents, amphetamines.
  • Atazanavir with antacids, proton pump inhibitors, H2 antagonists and some azoles.
  • Many counter-intuitive interactions are possible with low dose ritonavir or cobicistat so best to check every time!

Table 1 presents an overview of the ARV drugs which may affect/be affected by alterations in these PK mechanisms.

Table 1. Mechanisms of antiretroviral-associated drug interactions

Adapted from DHHS guidelines1

 

Drug by drug class

Pharmacokinetic interaction type

Absorption

Metabolism

Other mechanisms

Substrate

Inducer

Inhibitor

Integrase inhibitors

Bictegravir

Chelation decreases absorption

CYP3A4

UGT1A1

-

-

Inhibits transporters OCT2, MATE

Dolutegravir

Chelation decreases absorption

UGT1A1

CYP3A4 (minor)

-

-

Inhibits transporters OCT2, MATE

Raltegravir

Chelation decreases absorption

UGT1A1

-

-

-

Elvitegravir

Chelation decreases absorption

CYP3A4

CYP2C9

-

-

NNRTIs

Doravirine*

P-glycoprotein substrate

CYP3A4

-

-

-

Efavirenz

-

CYP2B6 (major), 3A4

CYP3A4, 2B6

CYP3A4, 2C19, 2C9

-

Etravirine

Inhibits P-glycoprotein

CYP3A4, 2C9, 2C19

CYP3A4

CYP2C9, 2C19

-

Nevirapine

-

CYP3A4, 2B6

CYP3A4, 2B6

-

-

Rilpivirine

Decreased by gastric acid lowering drugs

CYP3A4

-

-

Inhibits transporter OCT2

Pharmacokinetic enhancers

Cobicistat

Inhibits P-glycoprotein

CYP3A4, 2D6 (minor)

-

CYP3A4, 2D6

Inhibits OAT1B1, OAT1B3, MATE, BRCP

Ritonavir

Substrate and inhibitor of  P-glycoprotein

CYP3A4, 2D6 (minor)

UGT1A1, CYP1A2, 2B6, 2C8, 2C9, 2C19

CYP3A4, 2D6,2C9,2C19, 2A6, 1A2, 2E1

Inhibits OAT1B1, OAT1B3, MATE, BRCP

Protease Inhibitors

Atazanavir

Decreased by gastric acid lowering drugs

P-glycoprotein substrate, inhibitor and inducer

CYP3A4

-

CYP3A4, UGT1A1

Inhibits OATP1B1

Darunavir

P-glycoprotein substrate

CYP3A4

CYP2C9

CYP3A4

Inhibits transporter OATP

Fosamprenavir

P-glycoprotein substrate & inhibitor

CYP3A4

3A4 (weak)

CYP3A4

-

Lopinavir

P-glycoprotein substrate

CYP3A4

-

CYP3A4

Inhibits transporter OATP

Saquinavir

P-glycoprotein substrate & inhibitor

CYP3A4

-

CYP3A4

Inhibits transporter OATP

Tipranavir

P-glycoprotein substrate & inducer

CYP3A4

CYP3A4, 1A2, 2C19

CYP2D6

Inhibits transporter OATP

NRTIs

Abacavir

-

UGT1A1

-

-

Alcohol dehydrogenase substrate

Emtricitabine

-

-

-

-

-

Lamivudine

-

-

-

-

-

Tenofovir DF

P-glycoprotein substrate

-

-

-

Competition of active renal tubular secretion

Tenofovir AF

P-glycoprotein substrate

-

-

-

OATP substrate

Zidovudine

-

UGT enzymes

-

-

-

Entry inhibitors

Maraviroc

P-glycoprotein substrate

CYP3A4

-

-

-

Enfuvirtide

-

-

-

-

-

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/Adultand AdolescentGL.pdf. Accessed 25 July 2018, Table 17

‘-‘ indicates no clinically relevant interactions via these mechanisms

* Drug not yet commercially available in australia

 Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450; MATE, multidrug and toxin extrusion protein; OAT, organic anion transporter; OATP, organic-anion-transporting polypeptide; OCT, organic cation transporter; UGT, uridine diphosphate (UPD)-glucuronosyltransferase