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Page 24 of 39 Guideline

TDF + 3TC (or FTC) + EFV regimen). Assess the VL at metabolism and transport, which takes about 2 weeks to
6 months and follow standard guidance in response to be maximal and wanes in a similar time. Strong inducers
the result. (e.g. RIF, carbamazepine and phenytoin) can cause
significant decreases in concentrations of victim drugs,
Return after stopping a third-line regimen resulting in reduced efficacy. Pharmacokinetic interactions
are occasionally beneficial (e.g. RTV markedly increases
In patients returning to treatment after disengaging from a the concentrations of other PIs). Data on herb–drug
third-line regimen: interactions are very limited – both St John’s wort and
• Restart the same regimen and assess the VL at 6 months. garlic are known inducers. Clinically significant
Follow standard guidance in response to the result. pharmacokinetic interactions require dose adjustment of
the victim drug or, if the interaction is severe, avoiding
° Common pitfall: Performing a resistance test after
an ART treatment interruption of > 4 weeks. Such a co-administration with the perpetrator drug.
testing is of limited value. Many resistance mutations
are overtaken by the wild-type virus when ART is Overview of drug–drug interactions by
stopped and thus the resistance test may not accurately antiretroviral class
reflect the true resistance pattern. • NRTIs. These are generally neither victims nor perpetrators
of clinically significant pharmacokinetic interactions.
17. Drug–drug interactions • PIs. Ritonavir is a potent inhibitor of the key CYP enzyme
Key points 3A4 and the drug efflux transporter P-glycoprotein; it
also induces several other drug-metabolising enzymes
ÿ Whenever patients start or switch antiretroviral drugs or and drug transporters. Therefore, RTV-boosted PIs are
start new concomitant medications, it is important to frequent perpetrators of pharmacokinetic interactions,
evaluate potential drug interactions. but can also be victims of such interactions when co-
ÿ Many drugs and drug classes have clinically significant administered with strong inducers – co-administration
drug–drug interactions with ARVs. with strong inhibitors does not add significantly to the
ÿ There are also important drug interactions between inhibition by RTV. Atazanavir/ritonavir requires an acid
several ARVs. pH in the stomach for absorption – it should be taken 2 h
ÿ It is important to consult a regularly updated database to before or 1 h after antacids, and administration with PPIs
assess whether drugs can be co-administered and whether is not advised.
dose adjustment is required. • NNRTIs. These differ by individual drugs. Efavirenz is a
ÿ Herbal medications may also have interactions with moderate inducer. Rilpivirine can be the victim when co-
ART drugs (e.g. St John’s wort and garlic), but data on administered with strong inducers. Although inhibitors
herb–drug interactions are very limited. increase the exposure to RPV, it is seldom necessary to
adjust the dose. Etravirine induces CYP3A4 and also
Mechanisms of drug interactions inhibits two CYP enzymes; it can also be the victim when
co-administered with strong inducers.
There are two main mechanisms of drug–drug interactions: • InSTIs. Polyvalent cations (calcium, magnesium, iron
• Pharmacodynamic interactions: these interactions occur and aluminium) bind to InSTIs, reducing their absorption.
when one drug influences the action of another drug Integrase strand transfer inhibitors can be taken 2 h before
without altering its concentrations. Such interactions may or 6 h after polyvalent cations. However, calcium and
be either beneficial, if drug effects are additive or iron can be co-administered with InSTIs if taken with a
synergistic; or harmful, if drug effects are antagonistic. meal, but not in the fasted state. Integrase strand transfer
Additive toxicity is also a pharmacodynamic interaction inhibitors are victim drugs when co-administered with
(e.g. AZT and linezolid both cause myelosuppression and strong inducers. InSTIs are not perpetrator drugs, except
should not be co-administered). DTG that inhibits an efflux transporter important in the
• Pharmacokinetic interactions: these interactions occur when elimination of metformin (metformin dose should not
a perpetrator drug alters the concentrations of a victim exceed 500 mg 12 hourly).
drug by affecting its absorption, distribution, metabolism
or excretion. Inhibition is a direct chemical effect when a There are many important pharmacokinetic drug interactions
drug binds to the active site of drug-metabolising enzyme between ARVs and other drugs, as well as between different
or drug transporter – typically only one or a few enzymes ARVs. Some of these drug–drug interactions are discussed in
or transporters are inhibited. Inhibition is maximal when other sections of this article (e.g. interactions with RIF in
the inhibiting drug reaches steady state and wanes section 18). The full list of all potential drug interactions is
rapidly when the inhibiting drug is stopped. Strong very long and beyond the scope of this article.
inhibitors (e.g. ritonavir, clarithromycin and itraconazole)
can cause significant increases in the concentrations of Knowledge of drug interactions is constantly evolving.
victim drugs, resulting in toxicity. Induction results in Clinicians are advised to seek reliable information on drug–
transcriptional activation of many genes involved in drug drug interactions when using non-standard ART regimens

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