Page 184 - HIV/AIDS Guidelines

Drug Interactions (Last updated March 29, 2012; last reviewed March 27, 2012)
Potential drug-drug and/or drug-food interactions should be taken into consideration when selecting an
antiretroviral (ARV) regimen. A thorough review of current 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. Tables 14–16b
list significant drug interactions with different ARV agents and suggested recommendations on
contraindications, dose modifications, and alternative agents.

Protease Inhibitors (PIs) and Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

Most drug interactions with ARV drugs are mediated through inhibition or induction of hepatic drug
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metabolism. All PIs and NNRTIs are metabolized in the liver by the cytochrome P (CYP) 450 system,
particularly by the CYP3A4 isoenzyme. The list of drugs that may have significant interactions with PIs or
NNRTIs is extensive and is continuously expanding. Some examples of these drugs include medications that
are commonly prescribed in HIV-infected patients for non-HIV medical conditions, such as lipid-lowering
agents (e.g., statins), benzodiazepines, calcium channel blockers, immunosuppressants (e.g., cyclosporine
and tacrolimus), anticonvulsants, rifamycins, erectile dysfunction agents (e.g., sildenafil), ergot derivatives,
azole antifungals, macrolides, oral contraceptives, and methadone. Herbal products, such as St. John’s wort,
can also cause interactions that risk adverse clinical effects.

All PIs are substrates of CYP3A4, so their metabolic rates may be altered in the presence of CYP inducers or
inhibitors. Some PIs may also be inducers or inhibitors of other CYP isoenzymes and of 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 tipranavir/ritonavir (TPV/r) on CYP3A in vivo appears to be enzyme
inhibition. Thus, concentrations of drugs that are substrates for only CYP3A are likely to be increased if
given with TPV/r. The net effect of TPV/r on a drug that is a substrate for both CYP3A and P-glycoprotein
cannot be confidently predicted; significant decreases in saquinavir (SQV), amprenavir (APV), and lopinavir
(LPV) concentrations have been observed in vivo when given with TPV/r.
The NNRTIs are also substrates of CYP3A4 and can act as an inducer (nevirapine [NVP]), an inhibitor
(delavirdine [DLV]), or a mixed inducer and inhibitor (efavirenz [EFV]). Etravirine (ETR) is a substrate of
CYPs 3A4, 2C9, and 2C19. It is also an inducer of CYP3A4 and an inhibitor of CYPs 2C9 and 2C19. Thus,
these ARV agents can interact with each other in multiple ways and with other drugs commonly prescribed
for other concomitant diseases.
The use of a CYP3A4 substrate that has a narrow margin of safety in the presence of a potent CYP3A4
inhibitor may lead to markedly prolonged elimination half-life (t½) 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 inhibitory effect of ritonavir (RTV), however, can be beneficial when added to a PI, such as atazanavir
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(ATV), fosamprenavir (FPV), or indinavir (IDV). The PIs darunavir (DRV), LPV, SQV, and TPV require
coadministration with RTV. Lower than therapeutic doses of RTV (100 to 400 mg per day) are commonly
used in clinical practice as a pharmacokinetic enhancer to increase the trough concentration (C min ) and
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prolong the half-life of the active PIs. The higher C min allows for a greater C min : inhibitory concentration
(IC50) ratio, which reduces the chance for development of drug resistance as a result of suboptimal drug
exposure; the longer half-life allows for less frequent dosing, which may enhance medication adherence.

Coadministration of PIs or NNRTIs with a potent CYP3A4 inducer, on the other hand, may lead to
suboptimal drug concentrations and reduced therapeutic effects of the ARV agents. These drug combinations
should be avoided if alternative agents can be used. If this is not possible, close monitoring of plasma HIV
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents K-14

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