(Last updated:5/1/2014; last reviewed:5/1/2014)

Potential drug-drug and/or drug-food interactions should be taken into consideration when selecting an antiretroviral (ARV) regimen. A thorough review of concomitant medications can help in designing a regimen that minimizes undesirable interactions. In addition, the potential for drug interactions should be assessed when a new ARV is added to an existing ARV combination, as well as when any drug (including over-the-counter agents) is added to a patient’s medication regimen. Most drug interactions with ARV drugs are mediated through inhibition or induction of hepatic drug metabolism.1 The mechanisms of drug interactions with each ARV drug class are briefly summarized below. Tables 17–19b list significant drug interactions with different ARV agents and recommendations on contraindications, dose modifications, and alternative agents.

Protease Inhibitors

All protease inhibitors (PIs) are metabolized in the liver by CYP3A isoenzymes; consequently their metabolic rates may be altered in the presence of CYP inducers or inhibitors. Co-administration of PIs with ritonavir (RTV), a potent CYP3A inhibitor, intentionally increases PI exposure (see Pharmacokinetic Enhancing below).

Co-administration of PIs with a potent CYP3A inducer may lead to suboptimal drug concentrations and reduced therapeutic effects of the PI. These drug combinations should be avoided if alternative agents can be used. If this is not possible, close monitoring of plasma HIV RNA, with or without ARV dosage adjustment, and therapeutic drug monitoring (TDM), may be warranted.

Some PIs may also induce or inhibit CYP isoenzymes, P-glycoprotein (P-gp), or other transporters in the gut and elsewhere. Tipranavir (TPV), for example, is a potent inducer of CYP3A4 and P-gp. However, the net effect of ritonavir-boosted TPV (TPV/r) on CYP3A in vivo appears to be enzyme inhibition. Thus, concentrations of drugs that are substrates for only CYP3A are most likely to be increased if the drugs are given with TPV/r. The net effect of TPV/r on a drug that is a substrate of both CYP3A and P-gp cannot be confidently predicted. Significant decreases in saquinavir (SQV), amprenavir (APV), and lopinavir (LPV) concentrations have been observed in vivo when the PIs were given with TPV/r.

The use of a CYP3A substrate that has a narrow margin of safety in the presence of a potent CYP3A inhibitor, such as the PIs, may lead to markedly prolonged elimination half-life (t1/2) and toxic drug accumulation. Avoidance of concomitant use or dose reduction of the affected drug, with close monitoring for dose-related toxicities or TDM if appropriate, may be warranted.

The list of drugs that may have significant interactions with PIs is extensive and is continuously expanding. Some examples of these drugs include lipid-lowering agents (e.g., statins), benzodiazepines, calcium channel blockers, immunosuppressants (e.g., cyclosporine, tacrolimus), anticonvulsants, rifamycins, erectile dysfunction agents (e.g., sildenafil), ergot derivatives, azole antifungals, macrolides, oral contraceptives, methadone, and HCV protease inhibitors. Herbal products, such as St. John’s wort, can also cause interactions that increase the risk of adverse clinical effects. See Table 18a  for dosage recommendations.

Non-Nucleoside Reverse Transcriptase Inhibitors

All non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized in the liver by cytochrome P450 (CYP) 3A isoenzymes. In addition, efavirenz (EFV) and nevirapine (NVP) are substrates of CYP2B6 enzymes, and etravirine (ETR) is a substrate of CYP2C9 and 2C19 enzymes. Concomitantly administered drugs that induce or inhibit these enzymes can alter NNRTI drug concentrations, resulting in virologic failure or adverse effects. All NNRTIs, except rilpivirine (RPV), induce or inhibit CYP isoenzymes. EFV acts as a mixed inducer and inhibitor, but similar to NVP, it primarily induces CYP3A and 2B6 enzymes. ETR also induces CYP3A but inhibits CYP2C9 and 2C19 enzymes. The inducing effects of NNRTIs can result in sub-therapeutic concentrations of concomitantly administered drugs that are metabolized by CYP enzymes. Examples of such interacting medications include azole antifungals, rifamycins (e.g., rifabutin), benzodiazepines, hepatitis C virus (HCV) protease inhibitors, HMG-CoA reductase inhibitors (statins), and methadone. See Table 18b for dosing recommendations.

Integrase Strand Transfer Inhibitors

Raltegravir (RAL) is primarily eliminated by glucuronidation mediated by the uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 enzymes. Strong inducers of UGT1A1 enzymes (e.g., rifampin) can significantly reduce the concentration of RAL.2 Similar to RAL, dolutegravir (DTG) is also primarily metabolized by glucuronidation mediated by UGT1A1 and to a minor degree by CYP3A enzymes. DTG is also a substrate of UGT1A3, UGT1A9, and P-gp. Strong inducers of these proteins may reduce the concentration of DTG; alternatively, strong inhibitors of these proteins may increase the concentration of DTG. DTG does not appear to affect CYP or UGT enzymes or P-gp-mediated transport. In vitro, DTG has been shown to inhibit the renal organic cation transporter (OCT2), but does not appear to affect any additional transporter proteins.3

Elvitegravir (EVG) is metabolized largely by CYP3A enzymes but also undergoes glucuronidation by UGT 1A1/3 enzymes. It is available only as a fixed dose combination with cobicistat (cobi), tenofovir (TDF), and emtricitabine (FTC). Co-administration of EVG with cobi, a CYP3A inhibitor, increases EVG exposure (see Pharmacokinetic Enhancing below). Drugs that induce or inhibit CYP3A enzymes can alter concentrations of EVG. The co-formulation of EVG/cobi/TDF/FTC should not be co-administered with other ARVs because of potential drug interactions that may alter drug levels of EVG, cobi, or the concomitant drug.

Table 18d lists significant drug interactions and dosage recommendations when an INSTI is co-administered with other drugs.

Nucleoside Reverse Transcriptase Inhibitors

Unlike PIs, NNRTIs, EVG, and maraviroc (MVC), nucleoside reverse transcriptase inhibitors (NRTIs) do not undergo hepatic transformation through the CYP metabolic pathway. Significant pharmacodynamic interactions of NRTIs and other drugs, such as additive bone marrow suppressive effects of zidovudine (ZDV) and ganciclovir, have been reported. Pharmacokinetic (PK) interactions have also been reported; for example, atazanavir (ATV) concentration can be reduced when it is co-administered with TDF.4 However, the mechanisms underlying some of these interactions are still unclear. Table 18c lists significant interactions with NRTIs.

CCR5 Antagonist

MVC is a substrate of CYP3A enzymes and P-gp. As a consequence, the concentrations of MVC can be significantly increased in the presence of strong CYP3A inhibitors (such as RTV, cobi, and other PIs, except for TPV/r) and are reduced when MVC is used with CYP3A inducers (such as EFV or rifampin). Dose adjustment is necessary when MVC is used in combination with these agents (see Table 18e or Appendix B, Table 6 for dosage recommendations). MVC is neither an inducer nor an inhibitor of the CYP3A system and does not alter the PKs of the drugs evaluated in interaction studies to date.

Fusion Inhibitor

The fusion inhibitor enfuvirtide (T20) is a 36-amino-acid peptide that does not enter human cells. T20 is expected to undergo catabolism to its constituent amino acids with subsequent recycling of the amino acids in the body pool. No clinically significant drug-drug interaction with T20 has been identified to date.

Pharmacokinetic Enhancing

Pharmacokinetic (PK) enhancing is a strategy used in ARV treatment to increase the exposure of an ARV by concomitantly administering a drug that inhibits the specific drug metabolizing enzymes for which the ARV is a substrate. Currently two agents are used in clinical practice as PK enhancers: RTV and cobi.

RTV is an HIV PI that is primarily used in clinical practice at a lower than approved dose (100 to 400 mg per day) as a PK enhancer for other PIs because of its inhibitory effects on CYP450, predominately CYP3A4, and P gp. RTV increases the trough concentration (Cmin) and prolongs the half-life of the active PIs.5 The higher Cmin allows for a greater Cmin: inhibitory concentration ratio, which reduces the risk that drug resistance will develop as a result of suboptimal drug exposure. The longer half-life of the PI allows for less frequent dosing, which may enhance medication adherence. Even though the primary role of RTV is as a potent inhibitor of 3A4, it may also, to a less extent, induce CYP2C9, which may result in complex drug-drug interactions when used with PIs, other ARVs or non ARV drugs. Tables 18a and 19a–b list interactions between RTV-containing PI regimens and other medications, as well as comments on the clinical management of these interactions.

cobi is a specific, potent CYP3A inhibitor that has a weak to no effect on other CYP450 isoforms with no ARV activity. The high water solubility of cobi allows for its co-formulation with other agents.6 Cobi is currently available only as part of a fixed dose combination of EVG/cobi/TDF/FTC. cobi is used to increase the plasma concentrations of EVG, an INSTI. Like RTV, cobi has a complex drug-drug interaction profile. It also is an inhibitor of P-gp-mediated transport, which appears to be the mechanism by which cobi increases the systemic exposure to TDF. Table 18e lists interactions with cobi identified in PK studies conducted to date, projected interactions, and drugs that should not be co-administered with cobi.

When using RTV- or cobi-containing regimens, clinicians should be vigilant in assessing the potential for adverse drug-drug interactions. This is especially important when prescribing CYP3A substrates for which no PK data are available.


  1. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med. Mar 29 2001;344(13):984-996. Available at;db=PubMed&dopt=Citation&list_uids=11274626.
  2. Wenning LA, Hanley WD, Brainard DM, et al. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. Jul 2009;53(7):2852-2856. Available at;db=PubMed&dopt=Citation&list_uids=19433563.
  3. Tivicay [package insert]. Food and Drug Administration. 2013. Available at Accessed October 28, 2013.
  4. Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. Jun 2004;48(6):2091-2096. Available at;db=PubMed&dopt=Citation&list_uids=15155205.
  5. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother. Mar 1997;41(3):654-660. Available at;db=PubMed&dopt=Citation&list_uids=9056009.
  6. Xu L, Desai MC. Pharmacokinetic enhancers for HIV drugs. Curr Opin Investig Drugs. Aug 2009;10(8):775-786. Available at