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 |
– |
– |
– |
– |
– |
- 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