Drug Interactions with Antiretroviral Therapy (ART)

Possible drug-drug interactions should be taken into consideration when selecting an antiretroviral (ARV) regimen. A detailed review of concomitant medications can help in creating a regimen that minimizes undesirable interactions. The potential for drug interactions should be assessed when any new drug (including over-the-counter agents) is added to an existing ARV 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 are briefly mentioned below. Please refer to the content below[2] for lists of significant drug interactions with different ARV agents and recommendations on contraindications, dose modifications, and alternative agents[3] .

Mechanisms of Pharmacokinetic Interactions

Pharmacokinetic interactions that affect drug absorption include the following:

• Acid-reducing agents
• Products that contain polyvalent cations can bind to integrase strand transfer inhibitors (INSTIs) and reduce absorption
• Drugs that induce or inhibit the enzyme CYP3A4 or efflux transporter P-glycoprotein [P-gp] in the intestines

Pharmacokinetic interactions that affect hepatic metabolism occur via the following mechanisms:

• The cytochrome P450 enzyme system (most drugs)
• CYP3A4 is the most common enzyme responsible for drug metabolism
• The uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 enzyme: Metabolism of INSTIs dolutegravir (DTG) and raltegravir (RAL)
• The INSTIs bictegravir and dolutegravir have mixed metabolic pathways, including both CYP3A4 and UGT1A1

Pharmacokinetic enhancers (boosters) are used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. Currently, the 2 agents used include ritonavir (RTV) and cobicistat (COBI).

The role of drug transporters is evolving, revealing more drug interactions. For instance, DTG decreases the renal clearance of metformin by inhibiting organic cation transporters in renal tubular cells. Transporters aid hepatic, renal, and biliary clearance of drugs and may be susceptible to drug interactions. The influence of drug transporters on drug-drug interactions is complex and requires further understanding.

The principles above also apply to drugs that are substrates, inhibitors, and/or inducers of drug transporters (eg, P-glycoprotein [P-gp]). Other pharmacodynamic and pharmacokinetic mechanisms of interactions (eg, alteration of gastric pH, UGT1A1 metabolism) can affect ARVs. For more information regarding specific drug interactions, see the Medscape Drug Interaction Checker or the NIH Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.

For drugs that should not be coadministered with ARVs at any dose, see NIH Guidelines for the Use Drugs That Should Not Be Used with Antiretroviral Agents.

Non-nucleoside reverse transcriptase inhibitors

All non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized in the liver by CYP3A isoenzymes. Efavirenz (EFV) and nevirapine (NVP) also are substrates of CYP2B6 enzymes, and etravirine (ETR) is a substrate of CYP2C9 and CYP2C19 enzymes. Coadministration with drugs that induce or inhibit these enzymes can alter NNRTI drug concentrations, resulting in virologic failure or adverse effects.[4, 5]

All NNRTIs (except rilpivirine [RPV]) induce or inhibit CYP isoenzymes. EFV acts as a mixed inducer and inhibitor, but, similarly to NVP, it primarily induces CYP3A and 2B6 enzymes. ETR also induces CYP3A but inhibits CYP2C9 and 2C19 enzymes.

Examples of medications that interact with NNRTIs include azole antifungals (ketoconazole, itraconazole), rifamycins (eg, rifabutin, rifampin), benzodiazepines (eg, midazolam, triazolam), HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), and methadone.

For more information, see Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): DOR, RPV, EFV, ETR.

Table 1. NNRTIs Drugs and Their Metabolic Pathways ^[3] (Open Table in a new window)

Protease inhibitors

Protease inhibitors (PIs) are metabolized in the liver by CYP3A isoenzymes; therefore, their metabolism may be altered by CYP inducers or inhibitors. Coadministration of PIs with ritonavir (RTV), a potent CYP3A inhibitor, is used to intentionally increase PI systemic exposure (ie, pharmacokinetic enhancing, or ”boosting”).[6]

Coadministration of PIs with potent CYP3A inducers may result in 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, may be warranted.

Some PIs may also induce or inhibit other CYP isoenzymes, P-gp, or other transporters in the gut and elsewhere. Tipranavir (TPV) 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 may result in a prolonged elimination half-life and toxic drug accumulation. Avoid coadministration or reduce the dose of the affected drug, along with close monitoring for dose-related toxicities or measuring serum drug levels, if appropriate.

The list of drugs that may have significant interactions with PIs is extensive and continues to grow. Some examples of these drugs include lipid-lowering agents (eg, statins), benzodiazepines, calcium channel blockers, immunosuppressants (eg, cyclosporine, tacrolimus), anticonvulsants, rifamycins, erectile dysfunction agents (eg, sildenafil), ergot derivatives, azole antifungals, macrolide antibiotics, oral contraceptives, methadone, and HCV protease inhibitors. Herbal products (eg, St. John’s wort) can also cause interactions that increase the risk of adverse clinical effects.

For more information, see Boosted Protease Inhibitors (PIs): ATV, DRV.

Table 2. PIs and Their Metabolic Pathways ^[6] (Open Table in a new window)

Pharmacokinetic enhancers (boosting agents)

Pharmacokinetic (PK) enhancing is used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. Two agents are available in the United States for use as PK enhancers (ritonavir, cobicistat [COBI]). Both of these drugs are potent CYP3A4 inhibitors, resulting in higher drug exposures ARVs are metabolized by this pathway. Importantly, RTV and COBI may have different effects on other CYP or UGT metabolizing enzymes and drug transporters. Complex or unknown mechanisms of PK-based interactions preclude extrapolation of RTV drug interactions to certain COBI interactions, such as interactions with warfarin, phenytoin, voriconazole, oral contraceptives, certain HMG-CoA reductase inhibitors (or statins), and other drugs.[2]

For more information, see the NIH Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.

Table 3. Pharmacokinetic Enhancers and Their Metabolic Pathways ^[2] (Open Table in a new window)

Integrase strand transfer inhibitors

The main concern regarding interactions with integrase strand transfer inhibitors (INSTIs) is the potential for decreased absorption from the gut by polyvalent cations. If coadministration is necessary, give INSTI at least 2 hours before or at least 6 hours after supplements containing polyvalent cations, including but not limited to the following: cation-containing laxatives or antacids; Fe, Ca, or Mg supplements; and sucralfate. Monitor for virologic efficacy.[7, 8]

INSTIs are substrates of UGT1A1. Strong UGT1A1 inducers (eg, rifampin) may result in reduced INSTI plasma concentrations, resulting in treatment failure. Elvitegravir (EVG) is also a substrate of CYP3A4. Coadministration with CYP3A4 inducers may result in loss of virologic efficacy.[9]

The INSTIs bictegravir and dolutegravir have mixed metabolic pathways, including both CYP3A4 and UGT1A1. Drugs that induce or inhibit these enzymes may have variable effect on the PKs of these INSTIs.

The uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme is the primary enzyme responsible for the metabolism of the INSTIs cabotegravir and raltegravir. Drugs that induce or inhibit the UGT enzyme can affect the PKs of these INSTIs.

Several other drug transport proteins have been discovered, and families of these proteins include multidrug and toxin extrusion, organic cation transporter[15] , organic anion transporter, breast cancer resistance protein[16] , and organic anion transporting polypeptide (OATP) enzymes[17, 18]

For more information, see https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv

Table 4. INSTIs and Their Metabolic Pathways ^[7] (Open Table in a new window)

Nucleoside reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) do not undergo hepatic transformation through the CYP450. The following examples include significant interactions with NRTIs:[10]

• Contraindications: Didanosine with allopurinol or ribavirin results in increased didanosine-associated toxicity that includes fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis.

• Drugs that compete for renal tubular secretion (eg, adefovir, ganciclovir, valganciclovir) may increase tenofovir DF serum concentrations.

• Stavudine requires intracellular phosphorylation by cellular kinases to the active metabolite stavudine triphosphate. Zidovudine, doxorubicin, and ribavirin reduce the phosphorylation needed for stavudine to become active.

For more information, see https://www.hivguidelines.org/antiretroviral-therapy/ddis/#tab_3_3

CCR5 antagonists

Maraviroc (MVC) is a substrate of CYP3A enzymes and P-gp.[11]

MVC is neither an inducer nor an inhibitor of the CYP3A system and does not alter the pharmacokinetics of other drugs.

The concentration of MVC can be significantly increased when coadministered with strong CYP3A inhibitors (eg, ritonavir).

The concentration of MVC is reduced when coadministered with strong CYP3A inducers (eg, efavirenz, rifampin).

For more information, see https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/drug-interactions-between-ccr5?view=full

Fusion inhibitors

Enfuvirtide (Fuzeon, T20) is a 36–amino-acid peptide that does not enter human cells.[2]

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.[2]

Post-attachment inhibitor

Ibalizumab (IDB) is an anti-CD4 monoclonal antibody with unknown metabolism and drug interactions.

HIV-1 gp120-Directed Attachment Inhibitors

Fostemsavir (FTR), an HIV-1 gp120-directed attachment inhibitor, is a prodrug of temsavir (TMR). The effect on gp120-directed attachment inhibitor refers to TMR concentrations [12]

For more information see   https://www.hivguidelines.org/antiretroviral-therapy/ddis/#tab_3_4

Alternant recommendations for specific drugs

Lovastatin, simvastatin: May use pravastatin or fluvastatin, which have the least potential for drug-drug interactions (except for pravastatin with DRV/RTV); may use atorvastatin and rosuvastatin with caution (start with the lowest possible dose and titrate based on tolerance and lipid-lowering efficacy).

Rifampin: May use rifabutin with dosage adjustments.

Midazolam, triazolam: May use temazepam, lorazepam, or oxazepam.[1, 13]