skip navigation

Skip Nav

Clinical Guidelines Portal

skip navigation

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Drug Interactions


(Last updated:2/12/2013; last reviewed:2/12/2013)

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 any new drug (including over-the-counter agents), is added to an existing ARV combination. 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 14–16c list significant drug interactions with different ARV agents and recommendations on contraindications, dose modifications, and alternative agents.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

All 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 like 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, benzodiazepines, hepatitis C virus (HCV) protease inhibitors, HMG-CoA reductase inhibitors (statins), and methadone. See Table 15b for dosing recommendations.

Protease Inhibitors (PIs)

All 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. For example, the rifamycins (i.e., rifampin and, to a lesser extent, rifabutin) are CYP3A4 inducers that can significantly reduce plasma concentrations of most PIs.2,3 Rifabutin is a less potent CYP3A4 inducer than rifampin. Therefore, despite wider experience with rifampin use, rifabutin is generally considered a reasonable alternative to rifampin for the treatment of tuberculosis when used with a PI-based regimen.4,5 Table 15a lists dosage recommendations for concomitant use of rifamycins and other CYP3A4 inducers with PIs.

Some PIs may also induce or inhibit CYP isoenzymes, P-glycoprotein, or other transporters in the gut and elsewhere. Tipranavir (TPV), for example, is a potent inducer of CYP3A4 and P-glycoprotein. The net effect of ritonavir-boosted tipranavir (TPV/r) on CYP3A in vivo, however, 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-glycoprotein (P-gp) cannot be confidently predicted. Significant decreases in saquinavir (SQV), amprenavir (APV), and lopinavir (LPV) concentrations have been observedin 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, 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 risk adverse clinical effects. See Table 15a  for dosage recommendations.

Integrase Strand Transfer Inhibitors (INSTIs)

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.6 See Table 15e for dosage recommendations. Raltegravir does not appear to affect CYP or UGT enzymes or P-glycoprotein-mediated transport.

Elvitegravir (EVG) is available only as a fixed dose combination with cobicistat (COBI), tenofovir (TDF), and emtricitabine (FTC). EVG is metabolized largely by CYP3A enzymes but also undergoes glucuronidation by UGT 1A1/3 enzymes. 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. Examples of interacting drugs include those listed above for NNRTIs and PIs. See Table 15e for dosage recommendations.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Unlike PIs, NNRTIs, EVG, and maraviroc (MVC), 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.7 However, the mechanisms underlying some of these interactions are still unclear. Table 15c lists significant interactions with NRTIs.

CCR5 Antagonist

MVC is a substrate of CYP3A enzymes and P-glycoprotein. As a consequence, the concentrations of MVC can be significantly increased in the presence of strong CYP3A inhibitors (such as RTV 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 16bor 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. It 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 (PK) Enhancing

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 glycoprotein (P-gp). RTV increases the trough concentration (Cmin) and prolongs the half-life of the active PIs.8 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. Because RTV is a potent inhibitor, it may result in complex drug-drug interactions when used with PIs and with other ARVs or non ARVs. Tables 15a and 16a–c 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. COBI has no ARV activity. The high water solubility of COBI allows for its co-formulation with other agents.9 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. COBI 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 15e 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. 2001;344(13):984-996. Available at
  2. Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin and rifabutin drug interactions. Am J Med Sci. 2008;335(2):126-136. Available at
  3. Spradling P, Drociuk D, McLaughlin S, et al. Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak. Clin Infect Dis. 2002;35(9):1106-1112. Available at
  4. Singh R, Marshall N, Smith CJ, et al. No impact of rifamycin selection on tuberculosis treatment outcome in HIV coinfected patients.AIDS. 2013;27(3):481-484. Available at
  5. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167(4):603-662. Available at
  6. 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. 2009;53(7):2852-2856. Available at
  7. 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. 2004;48(6):2091-2096. Available at
  8. 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. 1997;41(3):654-660. Available at
  9. Xu L, Desai MC. Pharmacokinetic enhancers for HIV drugs. Curr Opin Investig Drugs. 2009;10(8):775-786. Available at