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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

A review of drug-drug interactions in older HIV-


infected patients

Aarthi Chary, Nancy N. Nguyen, Kimberly Maiton & Mark Holodniy

To cite this article: Aarthi Chary, Nancy N. Nguyen, Kimberly Maiton & Mark Holodniy (2017):
A review of drug-drug interactions in older HIV-infected patients, Expert Review of Clinical
Pharmacology, DOI: 10.1080/17512433.2017.1377610

To link to this article: http://dx.doi.org/10.1080/17512433.2017.1377610

Published online: 19 Sep 2017.

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EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2017
https://doi.org/10.1080/17512433.2017.1377610

REVIEW

A review of drug-drug interactions in older HIV-infected patients


Aarthi Charya,b*, Nancy N. Nguyenc,d*, Kimberly Maitond* and Mark Holodniya,b,e*
a
Department of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; bDivision of Infectious Diseases and Geographic
Medicine, Stanford University School of Medicine, Stanford, CA, USA; cDepartment of Pharmacy, Veterans Affairs Palo Alto Health Care System, Palo
Alto, CA, USA; dDepartment of Pharmacy Practice, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA,
USA; eOffice of Public Health Surveillance & Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

ABSTRACT ARTICLE HISTORY


Introduction: The number of older HIV-infected people is growing due to increasing life expectancies Received 14 July 2017
resulting from the use of antiretroviral therapy (ART). Both HIV and aging increase the risk of other Accepted 6 September 2017
comorbidities, such as cardiovascular disease, osteoporosis, and some malignancies, leading to greater KEYWORDS
challenges in managing HIV with other conditions. This results in complex medication regimens with ARV; drug interaction;
the potential for significant drug-drug interactions and increased morbidity and mortality. elderly; HIV; HIV
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Area covered: We review the metabolic pathways of ART and other medications used to treat medical pharmacology; review
co-morbidities, highlight potential areas of concern for drug-drug interactions, and where feasible,
suggest alternative approaches for treating these conditions as suggested from national guidelines or
articles published in the English language.
Expert commentary: There is limited evidence-based data on ART drug interactions, pharmacokinetics
and pharmacodynamics in the older HIV-infected population. Choosing and maintaining effective ART
regimens for older adults requires consideration of side effect profile, individual comorbidities, interac-
tions with concurrent prescriptions and non-prescription medications and supplements, dietary pat-
terns with respect to dosing, pill burden and ease of dosing, cost and affordability, patient preferences,
social situation, and ART resistance history. Practitioners must remain vigilant for potential drug
interactions and intervene when there is a potential for harm.

1. Epidemiology of HIV and aging a need to manage concurrent chronic medical conditions.
In one study, nearly 90% of HIV patients aged ≥55 years
The number of older human immunodeficiency virus (HIV)-
had one or more additional medical comorbidities, with an
infected people is growing with increasing life expectancies
average of 2.4 comorbid conditions, and a resultant aver-
among HIV-infected populations treated early with antire-
age of 2.7 non-ARV medications prescribed, per patient [5].
trovirals (ARVs) approaching those of HIV-uninfected popu-
By 2030, an estimated 28% of HIV-infected Dutch patients
lations [1]. In 2013, people age 55 years and older
will have ≥3 age-related, non-AIDS comorbidities, with
comprised 26% of people living with HIV in the United
nearly 80% predicted to be diagnosed with cardiovascular
States, with this number expected to rise. The ATHENA
disease, 17% with diabetes, and 17% with malignancies [2].
study estimated that by the year 2030, nearly three-quarters
This increased burden of comorbidities requires manage-
of Dutch patients on ARV therapy (ART) will be aged
ment across a broad range of specialties, increasing the
≥50 years [2]. Yet the care of older HIV-infected patients
risk of polypharmacy, interactions, and prescribing errors.
presents special challenges; people aged ≥55 years in the
According to a Centers for Disease Control and Prevention
United States are more likely to have late HIV disease, or
(CDC) study, the percentage of American adults taking ≥5
acquired immunodeficiency syndrome (AIDS), at the time of
drugs in the past 30 days increased from 4.0% in 1988–1994
HIV diagnosis, and disproportionately high rates of death
to 10.1% in 2007–2010 [6]. Polypharmacy, generally defined as
from HIV are seen among this age group [3]. In addition,
use of ≥5 concurrent medications or at least one potentially
both HIV and aging increase risk of other comorbidities,
inappropriate drug [7], is also highly prevalent among older
such as cardiovascular disease, osteoporosis, and some
HIV-infected adults (aged ≥50 years). In one study, HIV-
malignancies, leading to greater challenges in managing
infected patients consumed a median of 13 medications in
HIV. Even in the era of combined ART, morbidity attributed
contrast to 6 medications in the HIV-uninfected cohort [8].
to non-AIDS causes is more frequent, and a more likely
Among HIV-infected patients, 74% met criteria for polyphar-
cause of death, in people with well-controlled HIV com-
macy, and 52% received at least one potentially inappropriate
pared to their HIV-uninfected peers [4].
medication utilizing the American Geriatrics Society’s 2012
HIV-infected patients have a higher prevalence of cer-
Beers Criteria.
tain comorbidities, and with an aging population, there is

CONTACT Aarthi Chary aarthi.chary@va.gov Department of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
*These authors contributed equally to this work.
© 2017 Informa UK Limited, trading as Taylor & Francis Group
2 A. CHARY ET AL.

With polypharmacy among elderly comes increased risk for (NNRTIs) noncompetitively bind to viral reverse transcriptase,
medication-associated adverse effects; drug–drug, drug–food, halting transcription of viral RNA to DNA. Integrase strand
and drug–disease interactions; inappropriate prescribing or transfer inhibitors (INSTIs, or integrase inhibitors) prevent
dosing; and patient errors in dosing and timing [7,9]. Several transfer and integration of viral DNA into the human host
factors affect medication-associated morbidity and mortality in cell’s nuclear DNA. HIV-1 PIs prevent cleavage of inactive
an aging population. Physiologic changes accompanying viral long-chain proteins into active viral short-chain proteins
aging include: decreased renal and hepatic function (affecting and enzymes during viral assembly.
drug elimination), decline in lean body mass and total body Pharmacokinetic interactions which affect drug absorption,
water (affecting volume of distribution and elimination of distribution, metabolism, or elimination can lead to decreases
lipid-soluble drugs), declines in albumin (increasing protein- in systemic drug levels of ARV or other non-HIV drug therapies
unbound concentrations of many drugs), and diminished gas- resulting in treatment failure, while interactions that increase
tric blood flow (affecting absorption of drugs and drug meta- drugs levels can result in enhanced drug effects and toxicities.
bolism) [7,10]. Drug–disease interactions are also increased in Many clinically significant pharmacokinetic drug–drug interac-
older patients, such as potential effects of drugs on cardiovas- tions involve cytochrome P450 (CYP) enzyme metabolism
cular disease, cognition or mental status, and blood glucose. pathways in which drugs can be substrates, inhibitors, and/
Specific ARVs, such as abacavir and certain HIV-1 protease or inducers [26]. Enzymes commonly implicated in these inter-
inhibitors (PIs), may confer increased risk of cardiovascular actions are isozymes CYP3A4 as well as CYP2B6, CYP2C9,
disease [11–15]. Tenofovir, which has been associated with CYP2C19, and CYP2D6. Other CYP isozymes are involved as
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increased risk of bone and renal disease, may carry more drugs can be metabolized through more than one CYP path-
potential for harm in patients with additional risk factors for, way. Drug interactions arise when one drug either inhibits or
or early signs of, these comorbidities [16,17]. Similarly, while induces metabolism of a substrate drug via the CYP pathway,
serious hepatotoxicity rarely occurs with ARVs, it may be more thereby increasing or decreasing, respectively, the systemic
frequent among HIV-infected patients with alcohol use as well levels of the substrate drug. In some cases, complex bidirec-
as hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coin- tional interactions can be observed. Another metabolic path-
fection [18]. Behavioral and psychosocial factors may place way involved in drug interactions is the phase II
older patients with HIV at greater risk for medication-related glucuronidation pathway via the uridine-diphospho-glucoro-
problems. Furthermore, potential medication errors and poly- nosyltransferase (UGT) enzymes [27,28]. For example, systemic
pharmacy are magnified by communication barriers, including levels of INSTIs dolutegravir and raltegravir, which are UGT
deficits in vision, hearing, or cognition, and the presence of substrates, are significantly decreased with concurrent admin-
multiple prescribers or health-care providers. Perhaps surpris- istration of rifampin, a strong UGT inducer, thereby requiring
ingly, another factor contributing to higher rates of adverse dose-increases of either INSTI if coadministered or even a
events seen in HIV-infected patients ≥50 years old are higher change to an alternative agent if using the high-dose ralte-
rates of ARV adherence [19]. gravir formulation [29–33].
The impact and consequence of polypharmacy can be Drug transporters are another mechanism for ARV drug–
severe. The prevalence of drug–drug interactions involving drug interactions [34]. Relevant drug transporters, located in
ARVs range in reports from 20% to 50%, with up to one- various human body compartments include: P-glycoprotein (P-
third of patients determined to have a least one potentially gp), organic anion transporter (OAT), organic cation transpor-
serious or life-threatening interaction and increasing age as an ter (OCT), breast cancer resistance protein (BCRP), and multi-
independent risk factor for clinically significant drug interac- drug and toxin extrusion protein (MATE). Like CYPs, drugs can
tions [20–24]. In a review of over 5400 HIV-infected patients be substrates, inhibitors, and/or inducers of transporters.
enrolled in a single health plan, contraindicated combinations Table 1 lists ARVs by drug class and their individual inter-
involving ARV medications were found in 9.51 per 1000 new actions with CYP, UGT, and drug transporters [33,35–58]. In
prescriptions, among which 10% were associated with adverse general, NRTIs and the fusion inhibitor, enfuvirtide, are not
events [25]. As such, clinicians’ recognition of known and metabolized by CYP so drug interactions through this
potential drug–drug interactions involving ARVs is key to mechanism are not expected. Maraviroc, a CCR5 co-receptor
pharmacovigilance when managing older HIV-infected antagonist, is a major CYP3A4 substrate so requires dose
patients with polypharmacy and multiple comorbidities. adjustments when coadministered with drugs that are strong
CYP inducers or inhibitors, but does not itself exert inhibitory
or induction effects on CYP. The NNRTIs are generally CYP
inducers, except rilpivirine which is a CYP substrate without
1.1. Mechanisms of drug–drug interactions involving
CYP inhibition or induction activity. Both efavirenz and etra-
HIV ARVs
virine exhibit induction effects on CYP3A4 (resulting in
Currently, six ARV drug classes are available for HIV treatment. decreased levels of coadministered drugs which are CYP3A4
Entry and fusion inhibitors block the first steps in HIV infectiv- substrates) but also inhibit CYP2C9 and CYP2C19 isozymes
ity, preventing viral components from entering target human [41,42]. While generally associated with fewer drug interac-
cells. Nucleoside reverse transcriptase inhibitors (NRTIs) com- tions than other ARV classes, INSTIs dolutegravir and raltegra-
pete with naturally occurring nucleosides during HIV reverse vir are impacted by concurrent strong UGT enzyme inhibitors
transcription, causing chain termination and halting viral repli- and inducers; to a minor extent, strong CYP3A4 inhibitors or
cation. Non-nucleoside reverse transcriptase inhibitors inducers may also alter dolutegravir levels. Elvitegravir-
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Table 1. Metabolism and elimination of commonly used HIV antiretrovirals.


Metabolism and transporter effects
Drug class generic (abbreviation) Substrate Inducer Inhibitor Other mechanisms Elimination/excretion
Nucleoside reverse transcriptase inhibitor (NRTI)a
Abacavir (ABC) [35] – – – MRP2 inhibitor Eliminated through metabolism by alcohol dehydrogenase and
glucuronyl transferase
Emtricitabine (FTC) [36] – – – – Principally renal
Lamivudine (3TC) [37] – – – MRP2 inhibitor Active renal secretion via the organic cationic transport system
Tenofovir (TDF/TAF)b [38,39] – – CYP1A2 P-gp, BCRP substrate Renally cleared (70–80%). Eliminated by a combination of glomerular
filtration and active tubular secretion
Zidovudine (ZDV) [40] CYP2A6, CYP2C19, – – OAT3 substrate Primarily renal excretion following metabolism in the liver
CYP2C9, CYP3A4 (glucuronidation)
Non-nucleoside reverse transcriptase inhibitor (NNRTI)a
Efavirenz (EFV) [41] CYP3A4, CYP2B6 CYP2B6, CYP3A4 CYP2C9, CYP2C19 – Excreted primarily unchanged in feces, as metabolites in urine
(moderate) (moderate)
Etravirine (ETR) [42] CYP2C19, CYP2C9, CYP3A4 (moderate) CYP2C9, CYP2C19 – Unchanged etravirine mostly excreted in feces
CYP3A4 (moderate)
Nevirapine (NVP) [43] CYP3A4, CYP2B6, CYP2D6 CYP2B6 (moderate), CYP1A2 MRP2 inhibitor Glucuronide conjugation and urinary excretion of glucuronidated
CYP3A4 metabolites
Rilpivirine (RPV) [44] CYP3A4, CYP2C19, – CYP2C19 (moderate), – Primarily excreted via feces, trace amounts unchanged in urine
CYP1A2 CYP1A2, CYP2B6,
CYP3A4
Protease inhibitor (PI)
Atazanavir (ATV) [45] CYP3A4 – CYP3A4, CYP1A2, CYP2C8, – Primarily excreted in feces; 7% excreted unchanged in urine
CYP2C9, UGT1A1
Darunavir (DRV) [46] CYP3A4 – CYP3A4, CYP2D6 P-gp substrate & inhibitor Most excreted unchanged in feces
(moderate)
Fosamprenavir (FPV) [47] CYP3A4, CYP2C9, CYP2D6 – CYP3A4 (moderate), P-gp substrate Primarily excreted as metabolites in feces
CYP2C19
Indinavir (IDV) [48] CYP3A4, CYP2D6 – CYP3A4, CYP2C19, P-gp substrate Primarily excreted in feces, with some urine elimination; less than 20%
CYP2C9 of indinavir excreted unchanged
Lopinavir (LPV) [49] CYP3A – – – Co-formulated with ritonavir. Primarily excreted in feces; less than 3%
excreted unchanged in urine
Nelfinavir (NFV) [50] CYP2C19, CYP2C9, CYP2B6 CYP3A4, CYP1A2, – Majority excreted in feces
CYP3A4, CYP2D6 CYP2C19, CYP2C9
Ritonavir (RTV or /r) [51] Refer to Table 2: Comparison of ritonavir and cobicistat effects on CYP P450 isozymes and drug transporters Primarily excreted in feces; 11% excreted in urine
Saquinavir (SQV) [52] CYP3A4, CYP2D6 – CYP3A4, CYP2C19, P-gp substrate & inhibitor Rapid clearance through excretion in feces
CYP2C9
Tipranavir (TPV) [53] CYP3A4 CYP1A2, CYP2C19 CYP2D6, CYP3A4 P-gp inhibitor Mostly excreted in feces
Integrase strand transfer inhibitor (INSTI)
Dolutegravir (DTG) [54] CYP3A4 (minor), UGT1A1/ – – P-gp, BCRP substrate; Excreted in feces as unchanged drug and as metabolites in urine
3/9 OCT2 inhibitor
Elvitegravir (EVG) [55] CYP3A4, UGT1A1/3 CYP2C9 (weak/moderate) – – 95% of dose is recovered in feces, with hepatobiliary excretion
Raltegravir (RAL) [33] UGT1A1 – – – Eliminated mainly by metabolism via UGT1A1-mediated
glucuronidation in liver; some renal clearance
Fusion and entry inhibitors
Enfuvirtide (T-20) [56] – – – – Primarily eliminated via catabolism to its constituent amino acids
Maraviroc (MVC) [57] CYP3A4 – – P-gp substrate Mostly excreted in feces
Pharmacokinetic enhancer
Cobicistatc (COBI or /c) [58] Refer to Table 2: Comparison of ritonavir and cobicistat effects on CYP P450 isozymes and drug transporters Mainly excreted in feces
EXPERT REVIEW OF CLINICAL PHARMACOLOGY

MRP2: multidrug resistance-associated protein 2; UGT: UDP-glucuronsyltransferases; P-gp: P-glycoprotein; BCRP: breast cancer resistance protein; OCT2: organic cation transporter 2.
CYP (in bold lettering): major substrate or strong inhibitor/inducer.
a
Antiretrovirals not shown due to uncommon use in current clinical practice: NRTIs didanosine and stavudine, NNRTI delavirdine.
b
3

TDF: tenofovir disoproxil fumarate; TAF: tenofovir alafenamide.


c
Cobicistat does not have HIV-1 antiretroviral activity; it is used to pharmacokinetically enhance, or ‘boost,’ other antiretroviral drug levels.
4 A. CHARY ET AL.

containing ART regimens should always be evaluated for clini- particularly in patients with pre-existing chronic kidney dis-
cally significant drug–drug interactions primarily because elvi- ease. Notably, recent studies have demonstrated that regi-
tegravir requires coadministration with the pharmacokinetic mens containing a newer tenofovir prodrug, tenofovir
‘booster’ cobicistat to reach adequate therapeutic levels. alafenamide (TAF), which achieves higher concentrations in
Cobicistat, a potent CYP inhibitor, does not exhibit ARV activ- tissue with lower concentrations in plasma, are as effective
ity itself but is used to pharmacokinetically enhance levels of as similar TDF-containing regimens while having more favor-
other ARVs, such as INSTI elvitegravir and PIs atazanavir and able effects on both bone and kidney function [69]. It is
darunavir. Lastly, among ARVs, the PIs are implicated in the possible that some or all of the described pharmacodynamic
most drug–drug interactions as they are inhibitors of CYP3A4 drug interactions involving tenofovir nephrotoxicity or bone
and other CYP isozymes [24,59–61]. The PI ritonavir has the risks may be mitigated with the use of TAF instead of TDF in
most potent effect on CYP enzymes and is used in low doses the future; conversely, due to lower TAF plasma concentra-
(100–400 mg/day) as a pharmacokinetic ‘booster’ of other PIs. tions, drugs such as P-glycoprotein inducers rifampin, rifabu-
There are some distinct differences in the mechanisms and tin, St. John’s wort, boosted tipranavir, and some
potential impact of interactions involving ritonavir and cobici- anticonvulsants may cause more clinically significant reduc-
stat [62,64,65]; Table 2 compares CYP, UGT, and drug trans- tions in TAF levels compared to TDF levels. Overall, longitudi-
porter effects of ritonavir and cobicistat [51,58,62,63,66]. nal and thorough drug interaction data with TAF is largely
Ritonavir inhibits CYP3A4, CYP2D6, and P-gp, but may also lacking and – like any newer drugs – until more data is
exhibit dose- and time-related induction of CYP3A4 and P-gp available, close monitoring in consultation with an HIV specia-
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in addition to inducing CYP2B6, CYP2C9, CYP2C19, CYP1A2, list should still be performed in patients receiving any form of
and UGT [51,63]. Cobicistat demonstrates only inhibitory tenofovir, particularly with potential overlapping risk factors or
effects on drug transporters and certain CYP enzymes, primar- interactions [70].
ily CYP3A4 and to a lesser extent CYP2D6, but not CYP2C9, There are significant limitations to available evidence on ARV
CYP2C19, CYP2B6, or CYP1A2 [58,62,63]. In addition, UGT1A1 drug–drug interactions as data are often based on testing in
is induced by ritonavir, whereas cobicistat does not have healthy, HIV-uninfected individuals, although some information
UGT1A1 activity. Thus, drugs metabolized through the latter comes from Phase II–IV trials and post-marketing reporting. Only
CYP isozymes and UGT1A1 are affected by ritonavir but not certain drug combinations are tested in studies, so guidance on
cobicistat. It is important for clinicians to recognize these many drug–drug combinations used in clinical practice is either
differences and monitor for changes in efficacy or toxicity of theoretical or lacking. In such cases, knowledge of drug meta-
coadministered drugs when patients are transitioned from a bolism, CYP enzymes, and drug transporters is essential to
ritonavir- to a cobicistat-containing ARV regimen, or vice versa. anticipate potentially problematic interactions. It is also impor-
Lastly, drug interactions can be pharmacodynamic in nat- tant for clinicians to understand alterations in drug absorption
ure whereby use of drugs with similar toxicity profiles may occurring with changes in gastric pH or through drug binding or
result in overlapping or additive risks for drug-related adverse chelation. Clinicians should also be familiar with the compo-
effects. For example, tenofovir in the form of prodrug tenofo- nents in fixed-dose combination ARV pills to anticipate and
vir disoproxil fumarate (TDF) has been associated with both address possible drug–drug interactions (Table 3).
acute and chronic kidney disease, primarily proximal renal
tubulopathy, and at times associated with renal Fanconi syn-
drome [16,67,68]. Prescribers should consider avoiding coad- 2. Interactions with medications for common
ministration of drugs which independently carry significant comorbidities in HIV-infected older adults
potential for nephrotoxicity in conjunction with TDF,
Among older HIV-infected adults, cardiovascular medications
are the most commonly prescribed non-HIV medications, with
more than 50% of patients taking these medications in some
Table 2. Comparison of ritonavir and cobicistat effects by and on CYP P450
isozymes and drug transporters [51,58,62,63]. studies [21,24,71]. Other common classes of co-prescribed
CYP P450 medications include antidepressants, psychotropics, gastroin-
isozyme or drug testinal medications, and narcotic and nonnarcotic analgesics.
transporter Ritonavir Cobicistat Complementary and alternative medication use is also fre-
CYP 1A2 Substrate; inducer – quently reported [21,24]. Table 4 provides a summary of com-
CYP 2B6 Substrate; inducer –
CYP 2C9 Mixed inhibitor/inducer – mon ARV drug–drug interactions as well as suggestions for
CYP 2C19 Mixed inhibitor/inducer – managing or mitigating some of these interactions.
CYP 2D6 Substrate; inhibitor Substrate; inhibitor
CYP 3A4 Substrate; mixed inhibitor/ Substrate; inhibitor
inducer
P-gp Substrate; inhibitor Inhibitor 2.1. Cardiovascular medications: antiarrhythmics and
BCRP Inhibitor Inhibitor antihypertensives
OATP1B1 Inhibitor Inhibitor
OATP1B3 Inhibitor Inhibitor The antiarrhythmic amiodarone is a major CY3A4 substrate,
MATE1 Inhibitor Inhibitor
UGT1A1 Inducer – thus systemic amiodarone levels can be increased by potent
P-gp: P glycoprotein; BCRP: breast cancer resistance protein; OATP: organic CYP3A4 inhibitors such as PIs and cobicistat, resulting in
anion-transporting polypeptide; increased risk for EKG abnormalities, including QTc prolonga-
MATE: multidrug and toxin extrusion protein; UGT: UDP-glucuronosyltransferase. tion. This combination should be avoided as toxicity risk
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 5

Table 3. Fixed-dose combination antiretrovirals.


American and European trade name Agents contained within combination Antiretroviral drugs classes represented in combination
Combivir® Zidovudine + lamivudine NRTI
®
Trizivir Zidovudine + lamivudine + abacavir NRTI
®
Epzicom , Kivexa ® Lamivudine + abacavir NRTI
Truvada® Tenofovir DF + emtricitabine NRTI
Descovy® Tenofovir AF + emtricitabine NRTI
®
Atripla Efavirenz + tenofovir DF + emtricitabine NNRTI + NRTI
®
Complera , Eviplera ® Rilpivirine + tenofovir DF + emtricitabine NNRTI + NRTI
Odefsey® Rilpivirine + tenofovir af + emtricitabine NNRTI + NRTI
®
Stribild Elvitegravir + cobicistat + tenofovir DF + emtricitabine INSTI (+ PK booster) + NRTI
Genvoya ® Elvitegravir + cobicistat + tenofovir AF + emtricitabine INSTI (+ PK booster) + NRTI
Triumeq® Dolutegravir + abacavir + lamivudine INSTI + NRTI
®
Kaletra Lopinavir + ritonavir PI
Evotaz® Atazanavir + cobicistat PI (+ PK booster)
®
Prezcobix , Rezolsta ® Darunavir + cobicistat PI (+ PK booster)
Tenofovir DF: tenofovir disoproxil fumarate; Tenofovir AF: tenofovir alafenamide; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse
transcriptase inhibitor; INSTI = integrase strand transfer inhibitor; PI = protease inhibitor; PK booster = pharmacokinetic booster.

Table 4. Summary of drug–drug interactions involving HIV antiretrovirals and medications used to treat common medical comorbidities in aging.
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Medical condition Interacting drug combinations Drug interaction concerns and suggestions for management
Acid suppression for gastroesophageal reflux ● Antacids, H2-receptor antagonists, Proton ● Atazanavir and rilpivirine absorption significantly ↓ in setting of
disease (GERD) and peptic ulcer disease pump inhibitors + atazanavir, rilpivirine acid suppression, concern for virologic failure
(PUD) ● Cation-containing antacids + INSTIs ● INSTIs absorption ↓ in setting of concurrent cation-containing
antacids due to drug chelation
● Dose separation recommended if using antacids (for atazanavir,
rilpivirine, and INSTIs): take HIV medication at least 2 h prior to or
6 h after acid reducer medication
● AVOID coadministration of raltegravir with aluminum-magnesium
hydroxide antacids
● Dose separation recommended if using H2-receptor antagonists
(for atazanavir and rilpivirine): take HIV medication at least 2 h
prior to or 10–12 h after acid reducer medication
● Proton pump inhibitors (e.g. omeprazole) should be used with
extreme caution→ CONTRAINDICATED with rilpivirine; generally
avoid in certain patients on Atazanavir, e.g. HIV treatment-
experienced patients; no clinically significant interactions
expected with INSTIs
Anticoagulation ● Warfarin + PIs, NNRTIs, cobicistat ● Effects on warfarin levels can be erratic/variable, recommend
● DOACs + PIs, cobicistat close monitoring of INR to determine appropriate warfarin dose
in setting of antiretroviral therapy
● DOAC concentration expected to increase: potential increased
risk of bleeding; could consider dabigatran, edoxaban as may
have fewer interaction effects
Anxiety Benzodiazepines + PIs, cobicistat ● Generally safe to use concurrently: lorazepam, oxazepam,
temazepam
● Caution/monitor for benzodiazepine toxicity if used concurrently:
alprazolam, diazepam, clonazepam
● AVOID: triazolam, midazolam
Benign prostatic hypertrophy (BPH) Tamsulosin + ritonavir, cobicistat ● Tamsulosin levels may be ↑ by ritonavir, cobicistat: concurrent
(interaction also expected with silodosin, use generally NOT recommended
alfuzosin) ● Try to maximize dose of terazosin or prazosin first (note: dox-
azosin levels may be ↑ by ritonavir, cobicistat); consider tamsu-
losin only if benefits outweigh risks but monitor closely for side
effects
Depression SSRIs/TCAs + PIs, cobicistat ● PIs, cobicistat may cause ↑ or ↓ levels of SSRIs but clinical
significance variable; ↑ TCA levels expected
● In general, start with lowest dose of SSRIs/TCAs and titrate to
effect
Diabetes Metformin + dolutegravir (possibly with ● Significant ↑ metformin expected, manufacture recommends
elvitegravir/cobicistat also) limit metformin dose to no more than 1000 mg per day; use
clinical judgment and monitor closely if using higher metformin
dosages
Erectile dysfunction PDE-5 inhibitors + PIs, cobicistat ● PDE-5 inhibitors levels can significantly ↑; Recommended start
lowest dose, extend dosing interval
PDE-5 Initial dose Dosing
inhibitor interval
Sildenafil 25 mg Q48H
Tadalafil 5 mg (max single Q72H
dose = 10mg)
Vardenafil 2.5 mg Q72H
● Avoid concurrent nitrates; monitor for possible side effects of
PDE-5 inhibitor
(Continued )
6 A. CHARY ET AL.

Table 4. (Continued).
Medical condition Interacting drug combinations Drug interaction concerns and suggestions for management
Gout Colchicine + PIs, cobicistat ● Significant ↑ colchicine expected, use lower dose if treatment
necessary; avoid concurrent use in patients with renal or hepatic
impairment
Hyperlipidemia Statins + PIs, cobicistat ● AVOID Lovastatin, Simvastatin: significant (and potentially fatal)
↑ in statin levels by PIs; similar effects on statin levels expected
with cobicistat
● Statin with least significant drug interactions: Pitavastatin,
Pravastatin – however, caution with Darunavir as pravastatin
levels are ↑ by ritonavir
● Atorvastatin & Rosuvastatin: levels may be ↑, start/use lowest
effective dose, monitor for statin toxicity
Hypertension Calcium channel blockers + PIs, cobicistat ● Use caution with co-administration: ↑ levels of CCB expected
via CYP interaction
→ Amlodipine, felodipine, nifedipine + PIs, cobicistat: monitor
for hypotension, pedal edema
→ Diltiazem + atazanavir, atazanavir/ritonavir, atazanavir/
cobicistat: recommend ↓ diltiazem dose by 50%
Beta-blockers + PIs, cobicistat ● ↑ levels of metoprolol, carvedilol expected – Monitor for
hypotension, bradycardia; consider non-CYP metabolized beta-
blocker such as atenolol instead
Other cardiac meds Amiodarone + PIs, cobicistat ● Significant ↑ in amiodarone expected – DO NOT USE; otherwise
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use with extreme caution with careful monitoring for


amiodarone toxicity
Digoxin + PIs, cobicistat ● Digoxin levels may be ↑: monitor digoxin levels, toxicity
Dofetilide + dolutegravir ● ↑ dofetilide levels – AVOID. Consider alternative INSTIs:
raltegravir, elvitegravir
Pulmonary, Nasal ● Fluticasone, budesonide + ritonavir, ● Ritonavir, cobicistat can ↑ systemic levels of inhaled and
cobicistat intranasal fluticasone and budesonide (resulting in adrenal
● Salmeterol + PIs, cobicistat insufficiency and Cushing’s): concurrent use NOT recommended
→ Consider alternative lower potency inhaled or intranasal
steroid agents first (e.g. mometasone, beclomethasone,
triamcinolone)
● Salmeterol levels can be ↑ by PIs, cobicistat: concurrent use NOT
recommended due to increased risks for salmeterol-induced car-
diac side effects, consider formoterol instead
Pain ● Methadone + PIs, NNRTIs ● Monitor for possible Methadone withdrawal: methadone levels
● Oxycodone, fentanyl + PIs, cobicistat can be ↓ by NNRTIs and PIs – may require methadone dose
● Tramadol + PIs, cobicistat adjustments
● Codeine + PIs, cobicistat ● Oxycodone, fentanyl levels may be ↑ with PIs, cobicistat –
● TCAs + PIs, cobicistat consider lower doses of analgesics, monitor for opioid toxicity
● Tramadol analgesic effects may be ↑ or ↓ with PIs, cobicistat –
consider initiate at lower tramadol doses and titrate up to
analgesic effect
● Codeine analgesic effects may be ↓ with PIs, cobicistat – may
require uptitration of dosages or consider alternative opioid
agent
● TCA levels ↑ by PIs, cobicistat – consider alternative therapy for
treatment of neuropathy (e.g. gabapentin)
Seizures Carbamazepine, phenytoin, phenobarbital + ● Complicated bidirectional interactions (best to AVOID)
PIs, NNRTIs, cobicistat ● Consider alternatives such as levetiracetam and/or gabapentin as
these agents are not CYP metabolized
Sleep/Insomnia Trazodone + PIs, cobicistat ● Trazodone levels ↑ by ritonavir, cobicistat – start/use lowest
Zolpidem + PIs, cobicistat effective dose of trazodone (e.g. 25 mg/day)
● Zolpidem levels may ↑ – start at low dose
Herbals and natural supplements Commonly used and may be underreported, so clinicians should always ask patients about use. Potential for drug-
drug interactions with antiretrovirals and toxicities hard to predict as not routinely studied.
St. John’s wort + PIs, NNRTIs, dolutegravir, ● AVOID concurrent use: St. John’s Wort significantly ↓ levels of
elvitegravir antiretrovirals and increases risk for HIV treatment failure
↑: increase; ↓: decrease; PIs: protease inhibitors; NNRTIs: non-nucleoside reverse transcriptase inhibitors; INSTIs: integrase strand transfer inhibitors; CCB: calcium
channel blocker; PDE-5: phosphodiesterase-5; SSRIs: serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; CYP: cytochrome P450 enzyme.

outweighs benefits of therapy; if coadministration is necessary, Thus, raltegravir is an appropriate INSTI alternative to dolute-
close monitoring is required [70]. INSTI dolutegravir is an OCT2 gravir in this setting.
renal transporter inhibitor and can inhibit elimination of the Calcium channel blockers (CCBs) primarily undergo CYP3A4
antiarrhythmic dofetilide, increasing the risk for QTc prolonga- metabolism and are prone to interactions with ARVs, which
tion and life-threatening arrhythmias [54,72]; therefore, this inhibit or induce this enzyme. Studies have noted increased
combination is contraindicated. This effect is not expected systemic levels of nifedipine and amlodipine with concurrent
with other INSTIs, although elvitegravir’s need to be coadmi- PIs [73,74] and leg edema and orthostatic hypotension with
nistered with cobicistat would preclude its use with dofetilide combined felodipine-nelfinavir reported [75]. Levels of diltia-
due to cobicistat increasing dofetilide levels via CYP inhibition. zem were increased 2- to 2.5-fold when coadministered with
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 7

unboosted atazanavir; in combination with atazanavir, diltia- hypertriglyceridemia in HIV-infected patients without concerns
zem dose should be decreased by 50% [45,70]. When using for CYP interactions.
CCBs in patients receiving PIs or cobicistat, initiation with
lower CCB doses and monitoring of CCB effects are recom-
2.1.2. Cardiovascular medications: anticoagulation
mended. When coadministered with NNRTIs, which induce
Heparin and low-molecular weight heparins are not expected
CYP3A4, CCB dose up-titration may be needed [70].
to interact with ARVs. On the other hand, oral anticoagulants
With diuretics, angiotensin-converting enzyme inhibitors,
including warfarin and some direct oral anticoagulants
and angiotensin II receptor blockers (ARBs), CYP interactions
(DOACs) are extensively metabolized via CYP and therefore
are generally minimal. Close monitoring of renal function and
prone to interactions with certain ARVs.
electrolytes with concurrent tenofovir administration, particu-
Warfarin is a mixture of R-warfarin and S-warfarin;
larly TDF, is recommended although the interaction has not
S-warfarin has 3–5 times more potent anticoagulant effects
been studied. Among ARBs, losartan undergoes metabolism via
compared to R-warfarin and is primarily metabolized by
CYP2C9 and CYP3A4 and thus its levels may be decreased with
CYP2C9, while R-warfarin is primarily metabolized by CYP1A2
NNRTIs or increased with PIs and cobicistat [74]. Beta-blockers
and CYP3A4 [89,90]. Therefore, drugs that inhibit or induce
metoprolol and carvedilol are metabolized through CYP2D6
CYP2C9 have more impact on warfarin anticoagulant effects
and bradycardia with concomitant PIs has been reported [76].
than drugs acting on CYP3A4 alone. For example, warfarin
Thus, when beta-blocker therapy is warranted in patients taking
dosages of up to 20 mg/day were required to achieve ther-
PIs or cobicistat, clinicians should consider use of non-CYP-
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apeutic international normalized ratio (INR) in some patients


metabolized beta-blockers such as atenolol [70].
taking NNRTI nevirapine due to potent CYP3A4 induction of
warfarin metabolism [91,92]. In contrast, a much lower dose of
2.1.1. Cardiovascular medications: dyslipidemia warfarin 1.25 mg/day was used to achieve therapeutic INR in a
Drug interactions involving medications to treat dyslipidemia 34-year-old patient on NRTI efavirenz as a result of efavirenz
commonly involve HMG co-A reductase inhibitors (‘statins’) and inhibition of CYP2C9-mediated warfarin metabolism rather
ARVs, which inhibit the metabolism of statins. Of note, statins than its CYP3A4 induction [93].
are increasingly recommended for HIV-infected patients due to Despite their potent CYP3A4 inhibitory effects, ritonavir
findings of beneficial effects including decreased immune acti- and other PIs can lead to subtherapeutic INRs in patients
vation and formation of aortic plaques [77,78]; current, ongoing receiving warfarin, likely due to PIs’ CYP2C9 induction effects
investigations are evaluating use of statins to reduce risk of [92–94]. Additionally, INSTI elvitegravir induction of CY2C9-
cardiovascular disease in HIV-infected adults [79]. mediated warfarin metabolism appears to play a bigger role
Pharmacokinetic studies have shown dramatic increases in in drug interaction with warfarin than CYP3A4 inhibitory
statin levels with concurrent PI administration [80–82] and effects of cobicistat, resulting in a need for higher warfarin
cases of severe statin toxicities due to statin-PI coadministration dosages [95]. When switching ART, closer monitoring and
have been reported [83,84]. Two statins are contraindicated with follow-up of INR is warranted as warfarin levels may be
PIs and cobicistat-containing regimens: lovastatin and simvasta- affected in different directions by different ARVs. In addition,
tin. Although other statins interact with PIs and cobicistat, they older patients tend to need lower doses of warfarin to achieve
can be started at lower doses and titrated to tolerability and adequate anticoagulation compared to younger patients [96].
desired level of lipid-lowering intensity. Certain statins have Because of potentially problematic ARV drug–drug interac-
specific maximum dose recommendations with concurrent tions, further dosage adjustments in warfarin may be neces-
ARVs. For example, atorvastatin 10 mg daily with ritonavir- sary in older HIV-infected patients.
boosted darunavir results in atorvastatin serum levels equivalent Limited published data are available detailing ARV drug
to 40 mg atorvastatin alone [46]. Therefore, current recommen- interactions with the newer DOACs [97]. Levels of apixaban
dations are to not exceed atorvastatin 20 mg daily when used and rivaroxaban, both substrates of CYP3A4, may be increased
concurrently with ritonavir-boosted darunavir. Among statins, due to CYP inhibition by PIs and cobicistat or decreased due to
pravastatin is least likely to have drug interactions with PIs and CYP induction by NNRTIs. The latter was seen in a patient on
cobicistat since it is metabolized by CPY3A4 to only a minor nevirapine-based therapy who developed postsurgical deep
extent. However, serum levels of pravastatin were increased by vein thrombosis despite receiving the recommended dosage
63–81% when coadministered with ritonavir-boosted darunavir of rivaroxaban [98]. Dabigatran and edoxaban are not metabo-
[46]. Therefore, caution is advised when coadministering pravas- lized via CYP and therefore are DOAC options with lower drug
tatin with ritonavir- or cobicistat-boosted darunavir. Alternatives interaction potential. However, simultaneous administration of
to pravastatin in patients taking PIs or cobicistat include fluvas- cobicistat with dabigatran in 16 healthy volunteers resulted in a
tatin, atorvastatin, or rosuvastatin. Additionally, studies suggest 127% increase in dabigatran serum concentrations, likely as a
that pitavastatin levels are not significantly altered with concur- result of P-gp transporter interactions as dabigatran is a P-gp
rent PIs, thus making this agent another statin alternative [85,86]. substrate and cobicistat is a P-gp inhibitor [99].
Statin use with NNRTIs is generally safe although statin effective-
ness may be lessened due to NNRTI CYP induction [87,88].
For patients receiving fibrate or niacin therapy, close mon-
2.2. Diabetes medications
itoring for liver toxicity is advised given the possibility of
overlapping risks for hepatotoxicity with ART. Omega-3 fatty Management of diabetes in HIV-infected patients and HIV-
acids, or fish oil, are non-statin options for managing uninfected patients is similar although agents such as
8 A. CHARY ET AL.

metformin and rosiglitazone may have added benefit for treat- consideration should be made for short-acting agents that are
ing HIV-associated lipodystrophy, including in those without not extensively metabolized through the liver, such as loraze-
diagnosed diabetes [100,101]. Monitoring for lactic acidosis is pam, to minimize complications from enhanced benzodiazepine
recommended in patients receiving metformin and NRTIs, effects in patients taking PIs or cobicistat. For trazodone, a
especially in older patients with declining renal function and CYP3A4 substrate, current recommendations are to start with a
taking concurrent tenofovir, as both carry boxed warnings for low dose when coadministered with PIs due to a 240% increase
lactic acidosis [102–104]. Metformin also interacts with INSTI in trazodone concentrations by PI ritonavir [112].
dolutegravir through OCT2 located in renal tubules. Selective serotonin reuptake inhibitors (SSRIs), other anti-
Dolutegravir, an inhibitor of OCT2, led to lower renal clearance depressants, and antipsychotics are generally metabolized by
of metformin and subsequent increases in systemic levels of CYP though drug interactions with ARVs often involve CYP
metformin in healthy volunteers [105]. Current recommenda- isozymes other than CYP3A4 [108,113]. For example, fluoxe-
tions are to dose metformin no higher than 1000 mg/day tine, which is metabolized by CYP2C9, CYP2D6, and to a lesser
when given concurrently with dolutegravir [54,70]; however, extent CYP3A4, may be increased by PIs but lowered with
the clinical significance of this drug interaction and need for concurrent NNRTI nevirapine [114]. Citalopram and escitalo-
dosage adjustment has been questioned [106]. pram may be safer SSRI options in the setting of PI use [112];
ARV interactions involving other diabetes medications are however, clinicians should also be mindful of maximum dose
not well studied or documented; therefore, an understanding recommendations of no more than 20 mg daily in patients ≥
of metabolic pathways and drugs toxicities is helpful in antici- 60 years old due to increased risk for QTc prolongation at
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pating potential interactions [107]. Sulfonylureas are metabo- higher doses. Bupropion, which is metabolized by CYP2B6,
lized by CYP2C9 and their levels may be increased by NNRTIs may actually be decreased in the setting of concurrent ritona-
efavirenz and etravirine which inhibit CYP2C9, and decreased vir, which like NNRTI efavirenz can induce CYP2B6 and reduce
by PI ritonavir and INSTI elvitegravir which are CYP2C9 indu- bupropion efficacy [115–118]. Reports of adverse outcomes in
cers, but not affected by CYP3A4 inhibitor cobicistat [108,109]. patients taking atypical antipsychotics and ritonavir-boosted
Thiazolidinediones (TZDs) such as pioglitazone and rosiglita- PI regimens have been published [119–121]. Thus, close mon-
zone are metabolized by CYP2C8, CYP2C9, and CYP3A4 to itoring of antipsychotic medication effects, including meta-
varying degrees and therefore drug interactions involving bolic syndrome, QTc prolongation, and extrapyramidal
NNRTIs, PIs, and cobicistat should be anticipated. symptoms is warranted with ritonavir-, and possibly cobici-
Furthermore, increases in serum transaminases and rarely stat-containing regimens.
hepatic failure have been reported with TZDs; therefore,
close monitoring of liver function with concurrent ART, many
2.4. Pain management
of which are potentially hepatotoxic, should be employed.
The amylinomimetic pramlintide, alpha-glucosidase inhibi- Use of analgesics is common among older HIV-infected patients
tors (e.g. acarbose), and glucagon-like peptide-1 (GLP-1) [24]. Metabolism of opioid analgesics primarily involve CYP3A4
receptor antagonists (e.g. exenatide and liraglutide) have no and CYP2D6 isozymes [122], thereby increasing the risk for
known CYP interactions though gastrointestinal side effects of problematic ARV-analgesics drug interactions. In addition, cer-
these medications may limit their use in patients already tain agents such as codeine, morphine, oxymorphone, and
experiencing gastrointestinal intolerance from ART. hydromorphone also undergo glucuronidation via UGT2B7 and
Meglitinides such as nateglinide and replaglinide, as well as potentially other UGT isozymes [28,122]. For example, single-
dipeptidyl peptidase 4 (DPP-4) inhibitors such as linagliptin dose oxycodone concentrations were increased 2.6- to 3-fold
and saxagliptin, undergo CYP3A4 metabolism, therefore levels when coadministered with PIs ritonavir and lopinavir/ritonavir
of these agents may be affected by NNRTIs, PIs and/or cobici- [123]; however, the analgesic effects of chronically administered
stat and close monitoring of glucose levels and adjustments in oxycodone theoretically may be reduced in the setting of con-
dosages may be needed [107]. Among DPP-4 inhibitors, sita- current ritonavir due to induction of UGT conversion of oxymor-
gliptin is minimally metabolized by CYP3A4 and thus an phone, an active metabolite of oxycodone, to an inactive
option with minimal drug interactions [107,109]. The extent metabolite, although this interaction has not been studied.
of drug–drug interactions between sodium-glucose cotran- Levels of tramadol, which is metabolized by CYP3A4, are also
sporter 2 (SGLT2) inhibitors (e.g. canagliflozin and dapagliflo- expected to increase when used with ritonavir or cobicistat
zin) and ARVs is unknown; however, caution with concurrent [51,58]. Conversely, both codeine and tramadol are metabolized
NRTI tenofovir, particularly TDF, is warranted due to risk for via CYP2D6 to analgesically active metabolites and therefore
additive renal and bone toxicities [110]. their overall analgesic effects may be reduced in the setting of
ritonavir or cobicistat which also inhibit CYP2D6 [122]. As the
degree of CYP inhibition by HIV ARVs may vary between indivi-
duals and between CYP isozymes, alterations in opioid analgesic
2.3. Neuropsychiatric medications
levels can be difficult to predict. Close monitoring and preemp-
Benzodiazepines and nonbenzodiazepine hypnotics are on tive dose reductions may be necessary to avoid analgesic-
Beers Criteria list of potentially inappropriate medications due related adverse effects while uptitration of dosages may be
to increased risk for cognitive impairment and falls in older needed for optimal pain control. Although both INSTIs and the
patients [111]. When these drugs are required in older HIV- metabolite oxymorphone may be metabolized via UGT, the
infected patients, though they should generally be avoided, coadministration of dolutegravir or raltegravir with oxycodone
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 9

is not expected to result in significant interaction, though this peripheral neuropathy with concomitant use of stavudine
has not been specifically studied. and didanosine with vinca alkaloids [153].
NNRTIs may decrease opioid concentrations through CYP Vinca alkaloids, taxanes, epipodophyllotoxins, anthracy-
induction. For example, nevirapine and efavirenz induce clines, aromatase inhibitors, SERM modulators, irinotecan,
methadone CYP3A4-mediated metabolism resulting in metha- and most tyrosine kinase inhibitors are CYP3A4 substrates;
done concentration reductions of more than 50% with resul- therefore, interactions with PIs, cobicistat, and NNRTIs are
tant methadone withdrawal symptoms [124,125]. Methadone possible. Coadministration of vinca alkaloids with CYP3A4
levels may also be decreased with PIs [126–128], which is inhibitors increases the risk of neurotoxicity and severe mye-
contrary to expectations; patients should be monitored for losuppression; thus, boosted PIs should not be used with vinca
methadone withdrawal symptoms and loss of analgesia, and alkaloids [140]. On the other hand, vinca alkaloid concentra-
up-titrate doses as needed [129]. tions may be decreased by CYP3A4 inducers such as NNRTIs
Tricyclic antidepressants (TCAs), often used off-label to treat leading to reduced chemotherapeutic efficacy. Concomitant
neuropathic pain, are primarily metabolized through CYP3A4. docetaxel and PIs should be avoided, and paclitaxel with
When coadministered with PIs and NNRTIs, the lowest possible concurrent CYP3A4 inhibitors used with caution, due to
TCA dose should be used and adjusted based on clinical increased taxane concentrations; if coadministration is neces-
response and toxicity. Other agents used to treat neuropathic sary, patients should be closely monitored for severe myelo-
pain such as gabapentin and pregabalin are not expected to suppression [140,154]. Reports on tolerability of combined
interact with ARVs [130]. epipodophyllotoxins and PIs have been mixed, and coadmi-
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nistration with cobicistat has not been studied. However,


given the potential for increased epipodophyllotoxins concen-
2.5. Treatment of HCV infection
trations, due to CYP3A4 and possibly UGT1A1 interactions
With recent availability of oral direct-acting antiviral agents for with ARVs, close monitoring for chemotherapy-induced toxi-
HCV infection treatment, additional drug–drug interactions cities such as mucositis, transaminitis, and myelosuppression is
with HIV ARVs have come to the forefront. PI- and NNRTI- recommended [143,155]. Irinotecan, commonly used for treat-
based regimens as well as cobicistat-containing regimens are ment of HIV-related Kaposi sarcoma, should be used with
most likely to interfere with HCV therapies. Whenever possible, caution in patients taking atazanavir or indinavir as these PIs
selection of a non-interacting HIV regimen or a HCV regimen are potent inhibitors of glucuronidation, thereby increasing
without interacting agents is preferred. Many patients are cur- irinotecan concentrations and risk for severe neutropenia
rently on ART containing tenofovir, and it is important to [151]. Tyrosine kinase inhibitors are mainly metabolized by
recognize that ledipasvir, and possibly velpatasvir, may increase CYP3A4 and can interact significantly with PIs, NNRTIs, and
serum levels of tenofovir via inhibition of P-gp and BCRP, cobicistat. For example, erlotinib dose should be reduced from
thereby increasing risk for tenofovir-associated nephrotoxicity, 150 mg daily to 25 mg every other day with ritonavir and
particularly with TDF [131,132]. More extensive reviews of per- increased to 300 mg daily with efavirenz [150].
tinent and clinically significant drug–drug interactions between Cyclophosphamide, an alkylating agent commonly used in
HIV and HCV treatments are published elsewhere [70,132,133]. the management of Hodgkin’s and non-Hodgkin’s lymphoma
in HIV-infected patients, is a CYP2B6 substrate and may be
increased by PIs resulting in increased chemotherapeutic toxi-
2.6 Cancer chemotherapeutics
city such as neutropenia and mucositis [155].
HIV-infected persons are at risk for AIDS-associated malignan- Chemotherapeutic agents with lower potential for drug
cies, such as Kaposi sarcoma, cervical cancer, and non- interactions due to minimal CYP metabolism include antime-
Hodgkin’s lymphoma, as well as non-HIV-associated cancers, tabolites (such as 5-fluorouracil, methotrexate, and gemcita-
such as Hodgkin’s lymphoma, and lung and liver cancers [134]. bine) and platin derivatives. However, few clinical trials have
Before cancer chemotherapy is initiated in HIV-infected evaluated their interactions with ARVs [144]. While concurrent
patients, drug interactions with ARVs should be evaluated. PIs and antimetabolites are not associated with significant
Among ARVs, NNRTIs, PIs, and cobicistat have the highest changes in antimetabolite drug levels, additive renal toxicity
potential to interact with chemotherapeutic agents [135]. is possible with concurrent antimetabolites and the NRTI teno-
Because INSTIs have better tolerability, safety, and interaction fovir, particularly TDF, warranting closer renal function mon-
profiles, clinicians may consider changing ART to an INSTI- itoring [140,156]. In addition, use of these chemotherapeutic
based regimen in order to minimize potential interactions agents and ART should be monitored closely especially when
with cancer chemotherapy, a strategy which has demon- changes in weight, comorbidities, or hepatic and renal func-
strated feasibility in maintaining HIV suppression while treat- tion occur. Of note, 5-fluorouracil is a strong CYP2C9 inhibitor
ing cancer [136–139]. and can potentially increase NNRTI etravirine levels, leading to
Table 5 provides a summary of potential and known inter- peripheral neuropathy or hepatotoxicity [146].
actions as well as therapeutic considerations for coadminis- Systemic corticosteroids, commonly used as part of che-
tered ART and common chemotherapeutic agents [70,140– motherapeutic regimens, are also subject to drug interactions
152]. Of note, the table does not account for all potential with ARVs. Dexamethasone and prednisone are major CYP3A4
overlapping toxicities, the more common effects being bone substrates and coadministration with CYP inhibitors may
marrow suppression with coadministration of NRTI zidovudine increase a patient’s risk for hypercortisolism and Cushing’s
and most chemotherapeutic regimens, and additional syndrome. Thus, dexamethasone or prednisone should be
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10

Table 5. Interactions between HIV antiretrovirals and common cancer chemotherapy.


Metabolism, effects on CYP and elimination of Interacting antiretroviral Recommendations and other clinical
chemotherapeutic agent class Interaction safety Theoretical and/or actual interaction considerations
Vinca Alkaloids [140–142] Major substrate: CYP3A4 NRTIs (Zidovudine) X Zidovudine: Additive hematologic toxicity Avoid concurrent use with zidovudine.
(Vincristine, Vinblastine, P-gp
Vinorelbine) Elimination:
Predominantly feces
A. CHARY ET AL.

NNRTIs – No documented interactions. Efavirenz and Currently, no specific recommendations


etravirine should theoretically lower vinca
alkaloid levels
PIs M ↑ levels of Vinca alkaloids. May ↑ severity of Change to non-boosted regimen PI-regimen.
autonomic and peripheral neuropathy. Contraindicated with atazanavir, lopinavir, and
Ritonavir: ↓ cancer chemotherapeutic agent ritonavir.
levels. Other PIs: monitor for chemotherapeutic toxicity.
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat X ↓ cancer chemotherapeutic agent levels Currently, no specific recommendations
Taxanes [140,141] Major substrate: CYP3A4 2C8 NRTI – No documented interactions Currently, no specific recommendations
(Paclitaxel, Docetaxel) P-gp
Elimination:
Predominantly feces
NNRTIs (Delavirdine) M ↑ severity of myelosuppression, Monitor for chemotherapeutic toxicities
constitutional symptoms and peripheral
neuropathy
PIs X ↑ levels of taxane. ↑ severity of Avoid concurrent use with PIs.
myelosuppression, constitutional Tipranavir: monitor decrease in efficacy of
symptoms and peripheral neuropathy. chemotherapeutic agents
Tipranavir: ↓ cancer chemotherapeutic agent
levels.
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat DA ↓ metabolism of taxanes Consider therapy modification-50% taxane dose
reduction; monitor for chemotherapeutic
toxicity
Epipodophyllotoxins Major substrate: CYP3A4 NRTIs – No documented interactions Currently, no specific recommendations
[140,143] Minor substrate: CYP1A2, 2E1
(Etoposide, Teniposide) P-gp
Weak inhibitor: CYP2C9
Elimination:
Urine & feces
NNRTIs M ↓ cancer chemotherapeutic agent levels. Monitor for chemotherapeutic toxicities
Delavirdine: ↑ epipodophyllotoxins levels. ↑
risk and severity of mucositis,
myelosuppression and transaminitis
PIs M ↑ levels of epipodophyllotoxins. ↑ severity of Monitor for chemotherapeutic toxicities
mucositis and transaminitis with etoposide
and myelosuppression with etoposide and
teniposide.
Saquinavir: ↓ cancer chemotherapeutic agent
levels
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat DA ↓ cancer chemotherapeutic agent levels Consider dose adjustment of
epipodophyllotoxins
(Continued )
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Table 5. (Continued).
Metabolism, effects on CYP and elimination of Interacting antiretroviral Recommendations and other clinical
chemotherapeutic agent class Interaction safety Theoretical and/or actual interaction considerations
Anthracyclines [140,144– Major substrate: CYP3A4, 2D6 NRTIs (Zidovudine) X No documented interactions. Avoid concurrent use with zidovudine
147] P-gp Zidovudine: Additive hematologic toxicity
(Daunorubicin, Elimination:
Idarubicin, Predominantly biliary/feces
Doxorubicin)
NNRTIs – No documented interactions Currently, no specific recommendations
PIs X ↑ cancer chemotherapeutic agent levels. Avoid combination.
Tipranavir: ↓ cancer chemotherapeutic agent
levels. Atazanavir: contraindicated
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat CI ↓ cancer chemotherapeutic agent levels Avoid combination.
Platin derivatives Metabolism: NRTI (Tenofovir) DA No documented interactions. Consider dose adjustment of tenofovir
[140,144,146] Non-hepatic, nonenzymatic Tenofovir: additive renal toxicity
(Cisplatin, Carboplatin, Elimination:
Oxaliplatin) Predominantly urine
NNRTIs – No documented interactions Currently, no specific recommendations
PIs – No documented interactions Currently, no specific recommendations
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat – No documented interactions Currently, no specific recommendations
Alkylating agents
Cyclophosphamide Major substrate: CYP2B6 NRTI (Zidovudine) X No documented interaction. Avoid concurrent use with zidovudine.
[140,147,148] Minor substrate: CYP2A6, 2C19, 2C9 Zidovudine: additive hematologic toxicity
Weak/moderate inducer: CYP2C9
Elimination:
Limited urine & feces
NRTI M ↑ toxicity of cyclophosphamide Monitor for chemotherapeutic toxicities
(myelosuppression, nausea, and vomiting)
PIs (Darunavir) M Darunavir: ↑ risk of chemotherapy-induced Monitor for chemotherapeutic toxicities
mucositis, neutropenia and infection
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat X ↑ risk of chemotherapy-induced mucositis, Avoid combination
neutropenia and infection
Dacarbazine Major substrate: CYP1A2, CYP2E1 NRTIs (Tenofovir) M ↓ concentrations of Dacarbazine Monitor for efficacy of chemotherapeutic agent
[140,144,147] Elimination:
Predominantly urine
NNRTIs – No documented interactions Currently, no specific recommendations
PIs M Inhibition of CYP1A2 and CYP2E1 may ↓ Ritonavir: Monitor for chemotherapeutic
concentrations of Dacarbazine. Ex: Use of toxicities
concurrent ritonavir at therapeutic doses Other PIs: monitor for efficacy of
may ↑ formation of active metabolites and chemotherapeutic agent
↑ risk of nausea, vomiting, and
myelosuppression.
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat – No documented interactions Currently, no specific recommendations
Ifosfamide [149] Major substrate: CYP2B6 NRTIs – No documented interaction Currently, no specific recommendations
Minor substrate: CYP2C19, 2C8, 2C9, 3A4
Weak/moderate inducer: CYP2C9
Elimination:
Predominantly urine
EXPERT REVIEW OF CLINICAL PHARMACOLOGY

NNRTIs DA ↑ toxicity of ifosfamide (myelosuppression, Hold or change antiretroviral


arrhythmia, hemorrhagic cystitis)
(Continued )
11
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12

Table 5. (Continued).
Metabolism, effects on CYP and elimination of Interacting antiretroviral Recommendations and other clinical
chemotherapeutic agent class Interaction safety Theoretical and/or actual interaction considerations
PIs DA Inhibit ifosfamide activation. Hold or change to regimen without 3A4
Tipranavir: ↑ efficacy and toxicity of inhibition. Tipranavir: monitor for toxicity of
ifosfamide (myelosuppression, arrhythmia, chemotherapeutic agents
A. CHARY ET AL.

hemorrhagic cystitis)
INSTIs – No documented interaction Currently, no specific recommendations
Cobicistat X ↓ cancer chemotherapeutic agent levels Avoid combination
Antimetabolites
Cytarabine [144,146] Metabolism: NRTIs (Tenofovir) DA No documented interaction. Consider dose adjustment for renal toxicity
Hepatic via non-CYP mechanisms Tenofovir: additive renal toxicity
Elimination:
Predominantly urine
NNRTIs – No documented interactions Currently, no specific recommendations
PIs – No documented interactions Currently, no specific recommendations
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat – No documented interactions Currently, no specific recommendations
Fluoropyrimidines Metabolism: NRTIs – No documented interactions Currently, no specific recommendations
[144,146] Hepatic via non-CYP mechanisms
(Capecitabine, Strong inhibitor: CYP2C9
Fluorouracil (5-FU)) Elimination:
Predominantly urine
NNRTIs (Etravirine) M No documented interaction Etravirine: monitor for ARV toxicities
Etravirine: ↑ concentration of antiretroviral
PIs – No documented interactions Currently, no specific recommendations
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat – No documented interactions Currently, no specific recommendations
Methotrexate Substrate: BCRP, OAT3, P-gp, SLCO1B1 NRTIs (Tenofovir) M No documented interaction. Monitor for renal toxicity
[140,144,146] Elimination: Tenofovir: additive renal toxicity
Predominantly urine; consider dosage
reduction in renal dysfunction
NNRTIs – No documented interactions Currently, no specific recommendations
PIs – No documented interactions Currently, no specific recommendations
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat – No documented interactions Currently, no specific recommendations
Tyrosine kinase inhibitors
Erlotinib [150] Major substrate: CYP3A4 NRTIs – No documented interactions Currently, no specific recommendations
Minor substrate: CYP1A2
Inhibitor: UGT1A1
Elimination:
Predominantly feces
NNRTIs M/DA Delavirdine/efavirenz/etravirine: ↓ cancer Monitor for efficacy of chemotherapeutic agents
chemotherapeutic agent levels. Efavirenz/etravirine: ↑ Erlotinib dose from
Nevirapine/rilpivirine: ↑ cancer 150 mg to 200 mg, or up to 450 mg per day
chemotherapeutic agent levels
PIs M/DA ↑ levels of erlotinib. Saquinavir: ↓ cancer Monitor toxicity of chemotherapeutic agents
chemotherapeutic agent levels Ritonavir: Consider using erlotinib 25 mg
when coadministering with ritonavir 100 mg
daily.
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat X ↑ concentration of antiretroviral; ↑ cancer Avoid combination
chemotherapeutic agent levels
(Continued )
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Table 5. (Continued).
Metabolism, effects on CYP and elimination of Interacting antiretroviral Recommendations and other clinical
chemotherapeutic agent class Interaction safety Theoretical and/or actual interaction considerations
Imatinib [150] Major substrate: CYP3A4 NRTIs – No documented interactions Currently, no specific recommendations
Minor substrate: CYP1A2, 2C19, 2C8, 2C9,
2D6
P-gp
Moderate inhibitor: CYP3A4
Weak inhibitor: CYP2C9
Elimination:
Predominately feces
NNRTIs M ↑ levels of imatinib. Dose-related adverse Monitor for chemotherapeutic toxicities
events (fluid retention/weight gain, nausea,
vomiting, neutropenia)
PIs M ↑ plasma levels of imatinib. Dose related Monitor for chemotherapeutic toxicities
adverse events: fluid retention/weight gain,
nausea and vomiting, neutropenia.
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat X ↑ concentration of antiretroviral; ↑ cancer Avoid combination
chemotherapeutic agent levels
Maraviroc M ↓ metabolism of Maraviroc Monitor for antiretroviral efficacy
Sunitinib [150] Major substrate: CYP3A4 NRTIs – No documented interaction Currently, no specific recommendations
Inhibitor: P-gp
Elimination:
Predominantly feces
NNRTIs X ↑ cancer chemotherapeutic agent levels Avoid combination
Delavirdine: ↓ cancer chemotherapeutic
agent levels
PIs X ↑ cancer chemotherapeutic agent levels. Avoid combination
Tipranavir: ↓ cancer chemotherapeutic agent
levels
INSTIs (Elvitegravir) X No documented interaction. Currently, no specific recommendations.
Elvitegravir: ↑ cancer chemotherapeutic agent Elvitegravir: Avoid combination
levels
Cobicistat X ↑ cancer chemotherapeutic agent levels Avoid combination
Others
Irinotecan Major substrate: CYP3A4 NRTIs – No documented interactions Currently, no specific recommendations
[140,144,146,151] P-gp
Substrate:
UGT1A1
Elimination:
Limited urine and biliary/feces
NNRTIs M ↑ severity of myelosuppression. Monitor for chemotherapeutic toxicities
Etravirine: ↓ cancer chemotherapeutic agent
levels
PIs: M ↑ risk and severity of myelosuppression. Monitor for chemotherapeutic toxicities
Tipranavir: ↑ conversion to inactive
metabolites.
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat – No documented interactions Currently, no specific recommendations
Bortezomib [140,152] Major substrate: CYP3A4, 2C19 NRTIs – No documented interactions Currently, no specific recommendations
Minor substrate: CYP1A2, 2C9, 2D6
EXPERT REVIEW OF CLINICAL PHARMACOLOGY

Moderate inhibitor: CYP2C19


Weak inhibitor: CYP1A2, 2C9
Elimination:
Unknown
13

NNRTIs M ↑ cancer chemotherapeutic agent levels Monitor for chemotherapeutic toxicities


(Continued )
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14

Table 5. (Continued).
Metabolism, effects on CYP and elimination of Interacting antiretroviral Recommendations and other clinical
chemotherapeutic agent class Interaction safety Theoretical and/or actual interaction considerations
PIs M ↑ cancer chemotherapeutic agent levels. Monitor for chemotherapeutic toxicities
Tipranavir: ↓ cancer chemotherapeutic agent
levels
A. CHARY ET AL.

INSTIs – No documented interactions Currently, no specific recommendations


Cobicistat – No documented interactions Currently, no specific recommendations
Tamoxifen [140] Major substrate: CYP2C9, 2D6, 3A4 NRTIs – No documented interactions Currently, no specific recommendations
Minor substrate: CYP2A6, 2B6, 2E1
Moderate inhibitor: CYP2C8
Weak inhibitor: CYP2C9
P-gp
Elimination:
Predominantly feces
NNRTIs X ↓ levels of parent and metabolite, also ↓ PI Avoid combination. Use non-CYP3A4 dependent
levels. Use non-CYP3A4 dependent regimen
regimen
PIs X ↑ risk and severity of tamoxifen-related side Avoid combination. Use non-CYP3A4 dependent
effects (hot flushes, nausea, and vomiting). regimen
Use non-CYP3A4 dependent regimen
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat X ↑ risk and severity of tamoxifen-related side Avoid combination. Use non-CYP3A4 dependent
effects (hot flushes, nausea, and vomiting) regimen
Aromatase inhibitors Major substrate: CYP3A4 NRTIs – No documented interactions Currently, no specific recommendations
(Exemestane, Letrozole) Elimination:
[140] Urine & feces
NNRTIs M/X ↓ cancer chemotherapeutic agent levels. Monitor with delavirdine. Avoid concurrent use
Delavirdine: ↑ severity of musculoskeletal with efavirenz/nevirapine.
pain, constitutional symptoms, peripheral
edema
PIs M ↑ cancer chemotherapeutic agent levels Monitor for chemotherapeutic toxicities
INSTIs – No documented interactions Currently, no specific recommendations
Cobicistat M ↑ levels and severity of adverse effects Monitor for chemotherapeutic toxicities
(musculoskeletal pain, constitutional
symptoms, peripheral edema, hot flashes)
Corticosteroids [70,147] Major substrate: CYP3A4, P-gp NRTIs (Zidovudine) X No documented interaction. Avoid concurrent use with zidovudine.
(Dexamethasone, Weak/moderate inducer: CYP2A6, 2C19, 2C9 Zidovudine: Additive hematologic toxicity
Prednisone) Weak inducer: CYP3A4
UGT1A1
Elimination:
Predominantly urine
NNRTIs X ↑ risk of steroid related toxicity. ↓ levels of Avoid combination. Use non-CYP3A4 dependent
Etravirine. corticosteroid
PIs X ↑ risk of steroid related toxicity Avoid combination. Use non-CYP3A4 dependent
corticosteroid
INSTIs (Elvitegravir) M No documented interactions. ↓ elvitegravir Monitor for efficacy of elvitegravir
concentrations resulting in reduced
virologic response and viral resistance
Cobicistat X ↓ cobicistat concentration resulting in Avoid combination. Use non-CYP3A4-dependent
reduced virologic response and viral corticosteroid
resistance. ↑ dexamethasone
concentration
M: monitor; DA: dose adjustment necessary; X: avoid concurrent use; –; No data, ↑: increase; ↓: decrease.
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 15

used with caution in patients on PIs or cobicistat. Additionally, 2.8. Complementary and alternative medicine
dexamethasone exhibits CYP induction and could lower ARV
Studies report CAM use in 30–60% of HIV-infected patients
levels; therefore, HIV virologic responses need to be moni-
[168] and 78% of HIV-infected patients reported using CAM at
tored closely with concurrent therapy [70,147].
some point since their HIV diagnosis [169]. Common products
include St. John’s wort, milk thistle, garlic, ginseng, ginkgo
biloba, ginger, saw palmetto, and vitamin C [170]. Many herbal
2.7. Women’s health and men’s health and natural supplements have potential CYP and transporter
metabolism and effects although formal drug interaction stu-
Limited data is available regarding optimal management of
dies are often lacking. In addition, these supplements may
menopausal and postmenopausal women living with HIV
contain other ‘inactive’ or additional ingredients, such as poly-
infection. Data from drug interaction studies involving
valent cations, which may have interactions with ARVs
ARVs and hormonal contraceptives have demonstrated
(Section 2.10).
alterations in both estrogen and progesterone levels
Among herbal and natural products, St. John’s wort and
[70,147]. Such data is not currently available for hormone
garlic have the most documented interactions with ARVs,
replacement therapy. Therefore, when considering hormone
including reports of HIV treatment failure in patients initiating
replacement therapy in older HIV-infected women, weighing
St. John’s wort or garlic while on ART [170–174]. Ginkgo biloba
risks and benefits of therapy is advised and if hormone
has also been noted to reduce NNRTI efavirenz plasma con-
therapy is instituted, monitoring effectiveness and safety
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centrations by 38–62% resulting in treatment failure [175].


of therapy.
Therefore, it is generally recommended that patients avoid
When treating benign prostatic hypertrophy, clinicians
St. John’s wort, large amounts of garlic, and ginkgo biloba
should recognize that many alpha-1-adrenergic antagonists
while on ART. For a more detailed discussion regarding inter-
(‘alpha blockers’) are CYP3A4 substrates; therefore, systemic
actions between herbal supplements and ARVs, the reader is
levels are affected when coadministered with NNRTIs, PIs or
referred to the publication by Brooks and colleagues [171].
cobicistat. While interactions with terazosin, prazosin, and
doxazosin are less likely to be clinically significant, careful
dose titration is still appropriate with concurrent PIs or cobi-
2.9. Alcohol and recreational drugs
cistat due to potential for increased alpha blocker levels
[109]. Although no formal drug interaction study has been Per the CDC, prevalence of alcohol use, non-injection drug
conducted between alfuzosin or tamsulosin with PIs, the use, and injection drug use were 60.3%, 26.2%, and 2.5%,
interaction is expected to be clinically significant based on respectively, among HIV-infected persons [176]. Commonly
data demonstrating 2- to 3-fold increase in alpha blocker used recreational drugs include amphetamines, alcohol,
concentrations when coadministered with potent CYP3A4 cocaine, heroin, marijuana, and ketamine. Clinically significant
inhibitor ketoconazole [157,158]. Alfuzosin is contraindicated interactions with several recreational drugs have been
with PIs and cobicistat, whereas there are conflicting recom- reported in case series and pharmacokinetic studies [129].
mendations on concurrent use of tamsulosin with PIs and Dronabinol, an oral synthetic delta-9-tetrahydrocannabinol
cobicistat [159,160]. (THC), is often used for its appetite-stimulating and antiemetic
Phosphodiesterase-5 (PDE-5) inhibitors such as sildenafil, effects in both cancer and HIV-infected patients. THC is also
vardenafil, and tadalafil used for erectile dysfunction are meta- the active ingredient of smoked and ingested marijuana and is
bolized extensively by CYP3A4; therefore, coadministration partially metabolized by CYP3A4 and CYP2C9. Theoretically,
with PIs and cobicistat can lead to significant increases in concurrent use of ARVs that inhibit these CYP enzymes may
PDE-5 inhibitor serum levels [161–163]. Recommendations lead to enhanced THC effects including delusions, anxiety, and
are to start at lower dosages and increase the interval hallucinations. However, the clinically significance of this inter-
between doses of PDE-5 inhibitors to offset these drug inter- action has yet to be delineated [177].
actions. For example, when given concurrently with ritonavir, Ethanol can decrease NRTI abacavir metabolism, resulting
sildenafil should be dosed starting at 25 mg, with repeat doses in higher abacavir levels [35]. No dose adjustment in abacavir
taken at least 48 h apart from the previous dose [70]. is necessary with concurrent use, but closer monitoring is
In patients receiving levothyroxine while on a ritonavir- appropriate. Overlapping toxicities with alcohol use include
boosted PI regimen, levothyroxine dose increases may be hepatotoxicity with ARVs and increased risk of pancreatitis
necessary due to ritonavir induction of UGT-mediated when used with NRTI didanosine [178].
levothyroxine metabolism [164]. For HIV-infected women and 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is
men with osteopenia or osteoporosis, consideration should be an amphetamine-like compound that undergoes metabolism
given to switching patients on the tenofovir prodrug TDF to by CYP2D6. Concurrent use of MDMA and PI ritonavir, a
TAF, as improvements in bone mineral density have been potent inhibitor of CYP2D6, led to a fatal serotonergic reaction
noted in switch studies [69], or to a non-tenofovir containing in a patient whose serum concentration of MDMA was found
regimen [165–167]. Calcium supplements are often consumed to be 10-fold higher than expected [179]. Concomitant use of
by these patients and should be separated from certain INSTIs, ketamine (commonly referred to as ‘Special K’), which is meta-
the PI atazanavir, and the NNRTI rilpivirine as coadministration bolized by CYP2B6, along with efavirenz, nelfinavir, or ritonavir
may reduce absorption of these ARVs, potentially resulting in may result in ketamine toxicity; therefore, clinicians should
HIV treatment failure. counsel patients to avoid the combination [180,181].
16 A. CHARY ET AL.

Although ritonavir and cobicistat may increase systemic dolutegravir and supplements containing calcium or iron may
levels of a number of recreational drugs through CYP inhibi- be dosed simultaneously when taken with food [54,187].
tion, effects on cocaine and heroin levels may not be clinically As noted above, food may alter the absorption of some ARV
significant as CYP3A4 plays only a small role in the metabolism agents or regimens, at times to the extent that there are specific
of these agents [129,182]. recommendations regarding dosing with food. Ritonavir-
boosted atazanavir and ritonavir-boosted darunavir, and regi-
mens containing these drugs, should be taken with food, as
2.10 Interactions involving acid suppressants and
should elvitegravir-based regimens. Given exposure to rilpivirine
polyvalent cations
is reduced by 40% when given in a fasting state, it must be
Approximately 10–65% of HIV-infected patients use medica- given with a meal, ideally a moderate-to-high fat meal contain-
tions which involve the gastrointestinal tract, and even more ing at least 500 kcal. While absorption is modestly increased
take prescribed or over-the-counter vitamins or food supple- with food, dolutegravir may be administered with or without
ments. Concerning drug–drug interactions are highly preva- food and without regard to fat content [54,188]. Efavirenz
lent, especially between proton pump inhibitors and ARVs and plasma levels are adequate in the fasting state, whereas raised
between integrase inhibitors and polyvalent cations levels in the setting of food coadministration are associated with
[21,24,33,71,183]. Reductions in gastric pH from acid suppres- increase central nervous system side effects; thus, efavirenz-
sant use result in reduced systemic levels of PI atazanavir and based regimens should be taken on an empty stomach or with
NNRTI rilpivirine, which require an acidic environment for minimal food, particularly in patients newly prescribed efavirenz
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optimal absorption. In one pharmacokinetic study, atazanavir as this is when side effects are most commonly reported. The
concentrations were decreased by 48–62% after coadministra- remainder of ARVs currently used does not have specific recom-
tion of ranitidine or omeprazole [45,184,185]. In patients mendations for administration with or without food.
requiring acid suppressant therapy while on ART containing
atazanavir or rilpivirine, separation of drug administrations is
generally advised [70]; dose separation strategies are outlined 2.11. Interactions involving corticosteroids
in Table 3. Furthermore, proton pump inhibitor use is contra-
As previously discussed in Section 2.6, drug–drug interactions
indicated with rilpivirine as pharmacokinetic studies demon-
between common systemic corticosteroids and ARVs – primar-
strated 40% reduction in rilpivirine plasma concentrations
ily PIs – have been identified. Although inhaled and intranasal
when coadministered with omeprazole, raising concerns for
corticosteroids generally do not cause systemic effects, case
risk of virologic failure and HIV resistance [44,186].
reports have documented iatrogenic Cushing’s syndrome in
Concurrent use of INSTIs and polyvalent cations (e.g. cal-
patients receiving concomitant PI ritonavir and inhaled or
cium, magnesium, aluminum, zinc, and iron) commonly found
intranasal fluticasone, likely as a result of increased plasma
in over-the-counter multivitamins, mineral and nutritional sup-
fluticasone levels due to CYP3A4 metabolism inhibition by
plements, laxatives, and antacids can result in significantly
ritonavir [189–191]. Similar effects have also been noted with
decreased levels of integrase inhibitors. Integrase inhibitors
budesonide-ritonavir coadministration [192–194]. Thus, coad-
contain an ion chelating motif which predisposes them to
ministration of inhaled or intranasal fluticasone and budeso-
chelation with these cations, leading to decreased absorption
nide with PIs, as well as cobicistat due to its potent CYP3A4
and subtherapeutic INSTI levels. To minimize these interac-
inhibition, should be avoided where possible and alternative
tions, patients should generally be counseled to take the
corticosteroids such as beclomethasone, triamcinolone, and
INSTI at least 2 h before or 6 h after administration of poly-
flunisolide considered instead [70,195]. Of note, there have
valent cation products with one notable exception [70]. Based
been reported cases of adrenal axis suppression and clinically
on data demonstrating substantial lowering of plasma ralte-
significant Cushing’s syndrome in patients on ritonavir receiv-
gravir Cmin and AUC levels with both simultaneous and stag-
ing injectable triamcinolone [196,197] or topical ocular corti-
gered dosing of an aluminum-magnesium hydroxide antacid
costeroids [198,199].
(e.g. Maalox or Mylanta), coadministration of raltegravir with
Al–Mg hydroxide antacids is not recommended [33,70]. Similar
PK data of Al–Mg hydroxide dosed 4–6 h apart from other
3. Conclusion
integrase inhibitors is not available; in the absence of data,
coadministration of this antacid combination and dolutegravir Although ART has been extremely successful in controlling HIV
or elvitegravir should be avoided or undertaken with caution. infection, the HIV-infected population is aging, with the like-
There are dosing recommendations for dolutegravir and lihood of developing additional comorbid conditions such as
elvitegravir in combination with polyvalent cations. No dosing cardiovascular disease, diabetes, or cancer, and requiring addi-
separation is necessary when coadministering raltegravir with tional concomitant pharmacotherapy. Broadly, HIV medica-
calcium-carbonate antacids. Dolutegravir and elvitegravir tions are metabolized through a variety of mechanisms
should generally be dosed at least 2 h before or 6 h after including many different cytochrome isozymes and can either
antacids or other supplements containing polyvalent cations – induce or suppress isozyme activity. Significant drug–drug
including cation-containing laxatives; iron-, calcium- or mag- interactions are possible when ART is combined with addi-
nesium-containing supplements or vitamins; and sucrulfate – tional medications required in the treatment of comorbid
if coadministration is necessary. Given increased dolutegravir conditions, leading to toxicity or rendering medications inef-
exposure in the setting of food, particularly high-fat meals, fective. Knowledge of these metabolic pathways and possible
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 17

interactions prior to prescribing medications will reduce the Patients should be encouraged to obtain medications from
likelihood of serious side effects or loss of therapeutic potency. as few prescribing providers as possible, preferably all within a
single electronic medical record network. Dispensing of med-
ications from an integrated pharmacy should also be advo-
cated; the use of a specialty HIV pharmacy has been
4. Expert commentary
associated with decreased prescribing errors and improved
Choosing ARVs for HIV-infected individuals requires considera- adherence [204]. Creatinine clearance should be calculated
tion of side-effect profile, individual comorbidities, interactions using the Cockcroft-Gault method, although this equation
between concurrent prescription and/or non-prescription may be less accurate in older patients and those on stable
medications and supplements, dietary patterns with respect ART compared to the Modification of Diet in Renal Disease
to dosing, pill burden and ease of dosing, cost and affordabil- (MDRD) Study or Chronic Kidney Disease Epidemiology
ity, patient preferences, social situation, and ARV resistance Collaboration (CKD-EPI) equations [205,206]. Dose adjustment
history. All may be uniquely different in older HIV-positive for hepatic dysfunction can be facilitated by use of the Child-
patients compared to their younger HIV-infected peers. Pugh scoring system [207,208].
An assessment of drug interactions is one of many factors A multidisciplinary team involving an experienced HIV
that affects ARV regimen choice for older patients, and this pharmacist and other providers knowledgeable in HIV ART
carries significant complexities and potential for harm given has been associated with improved outcomes [209,210], and
the limited evidence-based data on drug interactions and numerous organizations have published guideline recom-
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pharmacokinetics in the older HIV-infected population. mendations for inclusion of pharmacists in caring for
Elderly patients are often underrepresented in clinical trials patients with HIV/AIDS [205,211,212]. They can also provide
due to physical, cognitive, and psychosocial barriers [200]. accurate renal and hepatic clearance estimations and assure
Even fewer data are available on elderly women, who are appropriate drug dosing based on age-related declines in
typically underrepresented in clinical trials upon which drug organ function. When data from clinical trials or pharmaco-
approvals are based [201,202]. Given most clinical and phar- kinetic studies regarding dose adjustment or drug interac-
macokinetics and/or pharmacodynamics trials are performed tions between specific drugs are lacking, an understanding
in younger patients and exclude patients with multiple comor- of drug metabolism, metabolic enzymes, and transporter
bidities, available published data and experience may not be systems is crucial; expert analysis and extrapolation from
generalizable to an older cohort with declining organ func- available data may be required in determining the need
tion, medication intolerability, increased comorbidities, com- for drug choice, dosing, and monitoring in elderly patients.
plex multidrug interactions, and greater frailty. In addition, these providers can provide one-on-one patient
Less is known about relationships between aging and ARV medication counseling, reduce premature discontinuation of
pharmacodynamic effects. It is probable that there are age- medications due to side effects that could instead be man-
related upregulation or downregulation of pharmacologic recep- aged by monitoring or symptom management, improve
tors, subtle changes in gut absorption and emptying, enzyme adherence through education and adherence aids (e.g. pill
activity, nutrition and albumin, gastric and central nervous sys- organizers, mobile apps or text messaging), and facilitate
tem blood flow, neuronal pathways, and subclinical changes in patient–prescriber communication. Other members of a mul-
organ function [10]. Resultant effects on absorption or tolerabil- tidisciplinary team which can uniquely benefit an aging HIV-
ity of medications in these settings, and possible need for addi- infected adult are: a psychologist including a provider able
tional dosing or monitoring precautions, are unknown. to perform neurocognitive assessments; social work and
Mechanisms to mitigate risks associated with ART in an case management to address issues of optimal housing,
aging population include: medication reconciliation and support, and safety in the home in the setting of increasing
review at each clinical visit with any provider, performing rates of isolation, elder abuse, financial stressors due to lack
routine assessment of drug interactions with the addition of of income, and physical/mental disability; and a provider
any new medication or supplement, discontinuing unneces- with expertise in gerontology.
sary medications or harmful combinations, and patient educa-
tion. When feasible, co-formulated medications are preferred
5. Five-year review
to decrease pill burden and pill fatigue, though not always
possible due to the need for frequent dosage adjustments. As the HIV-infected population ages, additional clinical and phar-
ARV drug interactions can be assessed using electronic macokinetic studies assessing drug interactions and tolerability
resources such as subscription drug databases Lexi-Comp® in older HIV-infected patients are needed, with greater efforts
(http://online.lexi.com/), MICROMEDEX® (http://www.microme toward novel recruitment and retention methods to engage
dexsolutions.com/), and Epocrates® (https://online.epocrates. patients aged ≥50 years, and even those aged >64 years, in
com/), as well as open-access resources including UHN large clinical trials. Given increasing recognition of the implica-
Toronto General Hospital Immunodeficiency Clinic’s drug tions of patient ‘frailty’ on clinical outcomes, integrating evolving
interactions tables (http://hivclinic.ca) and the University of data on the identification and prevention of frailty in HIV with
California, San Francisco HIVInSite website (http://hivinsite. ARV adherence and safety measures will be valuable to guide
ucsf.edu/) [203]. The University of Liverpool also hosts a HIV HIV-infected adults toward aging successfully and without dis-
drug interactions website (http://www.hiv-druginteractions. ability. From a clinical standpoint, decision support and point-of-
org), as well as a mobile application (app), ‘HIV iChart.’ care tools that can effectively assist in identifying and avoiding
18 A. CHARY ET AL.

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