Australian Commentary to the US DHHS Guidelines for the use of Antiretroviral Agents in Adults and Adolescents with HIV

US DHHS Guidelines with Australian Commentary

Table of Contents


DHHS Last Updated: September 2022Australian Commentary Last Updated: July 2023

  • ARVs requiring specific acidity (e.g. ATV and RPV) may also be affected by the physiological effects of oral supplementation – variable concentration-specific effects of supplementation on gastric pH and absorption of ARVs cannot be excluded as having interaction potential
  • RTV is also an inducer of glucuronosyl transferase (UDP-GT). For noting, RTV is a strong inducer of CYP 2C19, and strong inhibitor of 3A4/5 (especially with respect to agents extensively metabolised via 3A with high first-pass)
  • Cobi is a strong inhibitor of 3A4/5
  • EFV also a known 2C9 inhibitor
  • ETR also a known P-glycoprotein inhibitor
  • ABC is a substrate of P-glycoprotein, however due to absolute bioavailability, inhibition of P-gp is not likely to have a clinically significant effect on plasma ABC concentration

Useful resources for assessing clinical significance of drug-drug interactions:


Pharmacokinetic (PK) drug–drug interactions between antiretroviral (ARV) drugs and concomitant medications are common and may lead to increased or decreased drug exposure. In some instances, changes in drug exposure may increase the frequency and/or severity of toxicities or affect therapeutic responses. When prescribing or switching one or more drugs in an ARV regimen, clinicians must consider the potential for drug–drug interactions—both those affecting ARVs and those affecting concomitant drugs. A thorough review of concomitant medications in consultation with an expert in ARV pharmacology can help in designing a regimen that minimizes undesirable interactions. Recommendations for managing a specific drug interaction may differ depending on whether a new ARV is being initiated in a patient on a stable concomitant medication or a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of interactions are difficult to predict when several drugs with competing metabolic pathways and drug transporter systems are prescribed concomitantly. When it is necessary to prescribe interacting drugs, clinicians should be vigilant in monitoring for therapeutic efficacy and/or concentration-related toxicities. Tables 24a through 25b provide information on known or suspected drug interactions between ARV agents and commonly prescribed medications based on published PK data or information from product labels. The tables provide general guidance on drugs that should not be coadministered and recommendations for dose modification of ARVs or concomitant medicines or for alternative therapy.

Mechanisms of Pharmacokinetic Interactions

PK interactions may occur during absorption, metabolism, or elimination of the ARV and/or the interacting drugs. The most common drug interaction mechanisms are described and listed for individual ARV drugs in Table 23 below.

Pharmacokinetic Interactions Affecting Drug Absorption

The extent of oral absorption of drugs can be affected by the following mechanisms:

  • Acid-reducing agents—such as proton pump inhibitors, H2 antagonists, or antacids—can reduce the absorption of ARV drugs that require gastric acidity for optimal absorption (i.e., atazanavir and rilpivirine).
  • Products that contain polyvalent cations—such as supplements, iron products, or antacids that contain aluminum, calcium, or magnesium—can bind to integrase strand transfer inhibitors (INSTIs) and reduce absorption of these ARV agents.
  • Drugs that induce or inhibit the enzyme cytochrome P450 (CYP) 3A4 or efflux transporter P-glycoprotein in the intestines may reduce or promote the absorption of other drugs.

Pharmacokinetic Interactions Affecting Hepatic Metabolism

Two major enzyme systems are most frequently responsible for clinically significant drug interactions:

  • The CYP450 enzyme system is responsible for the metabolism of many drugs, including non-nucleoside reverse transcriptase inhibitors, protease inhibitors, the CCR5 antagonist maraviroc, and the INSTI elvitegravir. CYP3A4 is the most common enzyme responsible for drug metabolism, though multiple enzymes may be involved in the metabolism of a drug. ARV drugs and concomitant medications may be inducers, inhibitors, and/or substrates of these enzymes.
  • 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.
  • The INSTIs bictegravir and dolutegravir (DTG) and the capsid inhibitor lenacapavir have mixed metabolic pathways, including both CYP3A4 and UGT1A1. Drugs that induce or inhibit these enzymes may have variable impact on the PKs of these ARVs.

Pharmacokinetic Enhancers (Boosters)

PK enhancing is a strategy used to increase exposure of an ARV by concomitantly administering a drug that inhibits the enzymes that metabolize the ARV. Currently, two agents are used as PK enhancers: ritonavir (RTV) and cobicistat (COBI). Both drugs are potent inhibitors of the CYP3A4 enzyme and, thus, when coadministered with ARVs metabolized by the CYP3A4 pathway, the resultant systemic exposure of the ARVs is higher. Importantly, RTV and COBI 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, direct oral anticoagulants, phenytoin, voriconazole, oral contraceptives, and certain HMG-CoA reductase inhibitors (or statins).

Other Mechanisms of Pharmacokinetic Interactions

Drug transporters are expressed in various tissues, and they play an important role in drug disposition. Knowledge of drug transporters is evolving, elucidating additional drug interaction mechanisms. For example, DTG decreases the renal clearance of metformin by inhibiting organic cation transporters in renal tubular cells. Similar transporters aid hepatic, renal, and biliary clearance of drugs and may be susceptible to drug interactions. ARVs and concomitant medications may be inducers, inhibitors, and/or substrates of these drug transporters. The influence of drug transporters on drug–drug interactions is complex, and the clinical significance of these interactions is unclear but is under investigation. Further understanding of these pathways, and the clinical significance of this drug interaction mechanism is needed.

Role of Therapeutic Drug Monitoring in Managing Drug–Drug Interactions

Therapeutic drug monitoring (TDM) can guide the dosing of certain medications by using measured drug concentrations to improve the likelihood of desired therapeutic and safety outcomes. Drugs suitable for TDM are characterized by a known exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions.

When concomitant use of an ARV drug and another medication is likely to result in a clinically important drug–drug interaction, the first step is to assess whether other, equally effective treatment options can be used to avoid the interaction. If that is not possible, TDM may be useful in assessing whether a dose adjustment is needed.

Drug concentration assays for some ARV drugs are commercially available; however, result reporting may take 1 week or longer. When interpreting assay results, clinicians should consider the patient’s medication adherence, the timing of the patient’s last ARV dose and blood draw, and the time elapsed since coadministration of the interacting drug combination. If needed, a specialist in ARV clinical pharmacology should be consulted when interpreting the results and deciding what actions to take. If a dose adjustment is needed, TDM must be repeated after the dose-adjusted drug reaches steady state to assure appropriate dosing.

TDM information should not be used alone; it must be considered in conjunction with other clinical information—including virologic response, medication adherence, and signs and symptoms of drug toxicities—to assure safe and effective therapy.

Table 23. Mechanisms of Antiretroviral-Associated Drug Interactions

Pharmacokinetic interactions may occur during absorption, metabolism, or elimination of the antiretroviral (ARV) drug and/or the interacting drug. This table does not include a comprehensive list of all possible mechanisms of interactions for individual ARV drugs (e.g., transporters); however, the table lists the most common mechanisms of known interactions and focuses on absorption and cytochrome P 450 (CYP)– and uridine diphosphate glucuronosyltransferase (UGT) 1A1–mediated interactions.

Note: N/A indicates that there are no clinically relevant interactions by the mechanism. Identified mechanisms are specific to the ARV drugs described in the row and may not be reflective of complete ARV regimens. The older ARV drugs—fosamprenavir, nelfinavir, tipranavir, and zidovudine—are not commonly used in clinical practice and are not included in this table. Please refer to the U.S. Food and Drug Administration product labels for these ARVs for information regarding drug interactions.

ARV Drugs by Drug Class
Mechanisms That May Affect Oral Absorption of ARV Drugs
Enzymes That Metabolize or Are Induced or Inhibited by ARV Drugs
Increasing Gastric pH
Cationic Chelation
CYP Substrate
CYP Inhibitor
CYP Inducer
BICN/AConcentrations of PO INSTIs are decreased by products that contain polyvalent cations (e.g., Ca, Mg, Al, Fe, Zn).Substrate3A4N/AN/ASubstrate
DTGN/ASubstrate3A4 (minor)N/AN/ASubstrate
EVG/cN/AInhibitor3A43A4, 2D62C9Substrate
ATVConcentration decreasedN/ASubstrate, Inducer, Inhibitor3A43A4,
ATV/cConcentration decreasedN/ASubstrate, Inhibitor3A43A4, 2D6,
ATV/rConcentration decreasedN/ASubstrate, Inhibitor3A4, 2D63A4, 2D6,
1A2, 2B6,
2C8, 2C9,
ATV: Inhibitor
RTV: Inducer
DRV/cN/AN/ASubstrate, Inhibitor3A43A4, 2D6N/ANo data
DRV/rN/AN/ASubstrate, Inhibitor3A4, 2D63A4, 2D61A2, 2B6,
2C8, 2C9,
LPV/rN/AN/ASubstrate3A4, 2D63A41A2, 2B6,
2C8, 2C9,
(primary), 2A6, 3A4
3A43A4, 2B6,
NVPN/AN/AN/A3A4, 2B6N/A3A4, 2B6N/A
RPVOnly RPV PO: Concentration decreasedN/AN/A3A4N/AN/AN/A
Capsid Inhibitor
LEN (IM and PO)N/AN/ASubstrate3A43A4N/ASubstrate
CCR5 Antagonist
gp120-Directed Attachment Inhibitor
Fusion Inhibitor
Post-Attachment Inhibitor
Key: 3TC = lamivudine; ABC = abacavir; Al = aluminum; ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir; Ca = calcium; CAB = cabotegravir; CYP = cytochrome P; DOR = doravirine; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG/c = elvitegravir/cobicistat; Fe = iron; FTC = emtricitabine; FTR = fostemsavir; IBA = ibalizumab; IM = intramuscular; INSTI = integrase strand transfer inhibitor; LEN = lenacapavir; LPV/r = lopinavir/ritonavir; Mg = magnesium; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitors; NRTI = nucleoside reverse transcriptase inhibitors; NVP = nevirapine; Pgp = Pglycoprotein; PI = protease inhibitor; PO = oral; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; T-20 = enfuvirtide; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; UGT = uridine diphosphate glucuronosyltransferase; Zn = zinc
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