cyp3ainh&retrov

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doi: 10.1111/j.1365-2796.2010.02301.x
Drug–drug interactions in the treatment of HIV infection: focus
on pharmacokinetic enhancement through CYP3A inhibition
F. Josephson
MedicalProductsAgency,Uppsala,Sweden
Abstract.JosephsonF. (Medical ProductsAgency,Upp-
sala, Sweden). Drug–drug interactions in the treat-
ment of HIV infection: focus on pharmacokinetic
enhancement through CYP3A inhibition (Review-
Symposium).J InternMed2010;268: 530–539.
The aim of this review is to discuss the effect of phar-
macokinetic drug–drug interactions (DDIs) in the an-
tiretroviral treatment of HIV infection. In particular,
butnot exclusively,DDIsdue to thecytochromeP450
3A (CYP3A) inhibitor ritonavir, which is used to in-
crease antiretroviral drug exposure – a technique
known as pharmacokinetic enhancement or ‘ritona-
virboosting’ –willbereviewed.Theemphasisherewill
be on the treatment of important co-morbidities com-
mon in patients with HIV, including dyslipidaemia,
hypertension, tuberculosis and opiate dependence,
as well as on the potentially life-threatening interac-
tion between ritonavir and inhalational steroids, and
on the effect of acid-reducing agents on some antiret-
roviral drugs. Finally, further developments with re-
gard to theuse of CYP3A-blocking agents to augment
theefficacyofantiviral therapywillbediscussed.
Keywords: cobicistat, CYP3A, drug interaction, HIV,
ritonavir.
Introduction
Givenourunderstandingof thediseaseandtheavail-
able therapies, infection with human immunodefi-
ciency virus (HIV) currently requires lifelong therapy.
Combinations of three active drugs from at least two
classes are recommended in most cases. The most
commonly used combination regimens include two
nucleoside analogue inhibitors of reverse transcrip-
tase (NRTIs) incombinationwitheitheranon-nucleo-
side inhibitor of reverse transcriptase (NNRTI) or an
HIV protease inhibitor (PI) (Table 1). The potential for
clinically relevantdrug–drug interactions (DDIs)with
the NRTIs is limited andmainly restricted to interac-
tions between the NRTIs themselves; though, there
are some exceptions to this rule. With regard to the
NNRTIs, all three drugs currently approved in the
European Union (efavirenz, nevirapine and etravi-
rine) are inducers of cytochrome P450 (CYP450) en-
zymes and may in some cases cause clinically rele-
vant decreases in exposure to co-treating agents that
undergoCYP450-dependentmetabolism [1–3]. Addi-
tionally, they are metabolized by several different
CYP450 enzymes, and co-treatment with potent he-
patic enzyme inducers, such as rifampicin, may in
turn cause lowered NNRTI exposure. The generally
recommended PIs, including atazanavir, lopinavir
anddarunavir, arealmost exclusivelymetabolizedby
CYP4503A (CYP3A) and thereby biotransformed into
inactive metabolites [4–6]. To a varying extent, they
are themselves inhibitors of CYP3A, and some are
also inducers of hepatic drug-metabolizing enzymes.
Furthermore, and of crucial importance, all first-line
recommended PI regimens include co-administra-
tion of the CYP3A inhibitor ritonavir to increase the
pharmacokinetic exposure to the active PI through
increased bioavailability and decreased clearance
(lopinavir is co-formulated with ritonavir). This prac-
tice of pharmacokinetic enhancement is termed ‘ri-
tonavir boosting’ and has been shown to increase the
potencyandgreatlyaugment thebarrier to resistance
ofPI-basedantiretroviral therapy [7].
CYP3A, however, is not only responsible for the
metabolism of PIs, but is also the predominant en-
zyme for drug metabolism in general. Its substrates
include many important drugs used in a wide range
of therapeutic fields. Thus, ritonavir boosting creates
a plethora of putative, clinically relevant DDIs, as
illustrated inTable2.
In addition toNRTIs, NNRTIs andPIs, other currently
available drugs include the entry inhibitors enfuvir-
tide andmaraviroc, and the integrase inhibitor ralte-
gravir. The former drugshave relatively limiteduse in
Europe at present. Raltegravir, however, is a very po-
tent drug with a wide therapeutic index and is
increasingly used not only in treatment-experienced
530 ª 2010 The Association for the Publication of the Journal of Internal Medicine
Review |
but also in treatment-naive patients. Of interest, sig-
nificant DDIs are not commonly associated with ral-
tegravir, and it may be a valuable option when DDIs
arecomplicating thechoiceofantiretroviral agents.
Ritonavir
Ritonavir is itself a PI and was one of the first drugs
in this class to be approved for the treatment of HIV.
At therapeutic doses (400–600 mg twice daily), it is,
however, arguably the least well-tolerated PI, with
side effects including severe gastrointestinal symp-
toms, as well as increased plasma levels of choles-
terol and triglycerides [8, 9]. As mentioned previ-
ously, ritonavir is also a very strong inhibitor of
CYP3A. At considerablymore tolerable, though byno
means side effect–free, doses of 100 mg once or twice
daily, which are used for ritonavir boosting, hepatic
CYP3A activity is blocked by >80% and presystemic
CYP3A even more so, using midazolam or alfentanil
as a probe [10, 11]. Near-maximal CYP3A blockade
is seen at doses as low as 50 mg [12]. Ritonavir
boosting increases the area under the concentra-
tion–time curve (AUC) 5- to 80-fold, depending on
which ‘therapeutic’ PI is boosted. The highest values
are seen for substances suchas darunavir and lopin-
avir. The bioavailability of these agents in the ab-
sence of ritonavir is very low as a result of presystem-
ic metabolism, and therapeutic exposure cannot be
reached in the absence of profound CYP3A blockade
[4, 5, 13–15].
The DDI potential of ritonavir-boosted PI drug regi-
mens is complicated by the fact that ritonavir is not
only a strong net inhibitor of CYP3A but is also a po-
tent pregnane X receptor activator. It is therefore an
inducer of a number of clinically important drug-
metabolizing enzymes, including CYP1A2, CYP2C9,
CYP2C19, CYP3A and glucuronyl transferases [8,
11].Furthermore, it isan inducer aswell as an inhibi-
tor of transmembrane drug transporter p-glycopro-
tein [16, 17]. At therapeutic but not boosting doses, it
is also a significant inhibitor of CYP2D6 [8]. Owing to
the capacity of ritonavir (as well as some of the thera-
peutic PIs) to induce hepatic enzymes, the spectrum
of clinically relevant potential DDIs with ritonavir-
boosted PI regimens is not restricted to the risk of
substantially increased drug exposure and toxicity
because of CYP3A inhibition, but also in some cases
includes the possibility of decreased exposure and
therapeutic efficacy because of the induction of other
hepatic enzymes.
PI and statin therapy
Co-treatment with lipid-lowering therapy is common
amongstpatients treated forHIV infection.Dyslipida-
emia is frequent in thegeneralpopulationandmaybe
more so amongst individuals with HIV, regardless of
treatment [18]. Also, several antiretroviral agents are
associated with alterations in plasma lipids. Of
importance,most PIs, including ritonavir at boosting
doses, may cause increased total cholesterol,
Table 1 Examples of recommended and alternative first-line antiretroviral treatment regimens (e.g. see European AIDS Clinical
Societyguidelines,availableathttp://www.europeanaidsclinicalsociety.org/guidelines.asp)
NNRTI-basedregimens MajorpharmacokineticDDIpotential
NRTI NRTI NNRTI
abacavir + lamivudine + efavirenz
tenofovir + emtricitabine + efavirenz
Reducedexposure toco-treatingagentsbecauseof inductionof
drug-metabolizingenzymes.ReducedexposuretoNNRTIbecauseof
enzyme inductionbyco-treatingagent.
PI-basedregimens
NRTI NRTI PI ⁄ ritonavir (r)
abacavir + lamivudine + atazanavir ⁄ r
abacavir + lamivudine + darunavir ⁄ r
tenofovir + emtricitabine + atazanavir ⁄ r
tenofovir + emtricitabine + darunavir ⁄ r
Increasedexposure toco-treatingagentsbecauseofCYP3A inhibition.
Reducedexposure toco-treatingagentsbecauseof inductionof
drug-metabolizingenzymes.
Integrase inhibitor (II)-basedregimensNRTI NRTI II
tenofovir + emtricitabine + raltegravir
F. Josephson | Review-Symposium: Drug–drug interactions in the treatment of HIV infection
ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 268; 530–539 531
Table 2 Examples of drugs that undergo CYP3A-dependent
metabolism, which are contraindicated or should be used
with cautionwhen co-treatingwith a ritonavir-boosted PI (list
based on the European SPC for Norvir� [8], but note that the
list isnotexhaustive)
Drugsundergoing
CYP3A-dependent
metabolism Comments
Alpha-receptor
blockers
Detailsof themetabolismofother
drugs in thisclass, suchas
terazosinanddoxazocin,have
notbeenreported; theymayalso
beCYP3Asubstrates
Alfuzosin
Opiates CYP3Aisnot involved inmorphine
metabolism
Pethidine
Fentanyl
Anti-arrhythmics Therisksof co-administrationof
QT-prolongingagentsthatare
CYP3Asubstrates, together
withstrongCYP3Ainhibitorssuch
asritonavir,maybequite considerable
Amiodarone
Bepridil
Quinidine
Anticancer
agents
Notethatanumberofotheranticancer
agentsarealsoCYP3Asubstrates
Vincristine
Vinblastine
Anticonvulsants CYP3Aisnotprimarily involved in
themetabolismofvalproicacid
and lamotrigine
Carbamazepine
Antihistamines Cetirizine,whichhasconsiderable
renal elimination,maybea
preferredalternative
Astemizole
Terfenadine
Calciumchannel
antagonists
See text.Themagnitudeof
increasedexposureprobably
variesbetweenagents.Therisksof
co-administrationwith ritonavirmay
behigherwithagents thataffect
cardiacconductionat therapeuticdoses
Table 2 (Continued)
Drugsundergoing
CYP3A-dependent
metabolism Comments
Amlodipine
Felodipine
Nifedipine
Diltiazem
Verapamil
Gastrointestinal
motilityagents
Seeabove,anti-arrhythmics
Cisapride
Statins Seetext.Appropriatestatindepends
onwhichboostedPI isused
Simvastatin
Lovastatin
Atorvastatin
Immunosuppressants Considerable increase in
immunosuppressantexposure.
Co-treatment ispossible,however,
withcareful titrationanduseof
therapeuticdrugmonitoring
Cyclosporin
Tacrolimus
Everolimus
PDE-5 inhibitors Co-treatwithcaution,using
reduceddosesofPDE5inhibitors
Sildenafil
Tadalafil
Vardenafil
Benzodiazepines In contrast to the listed benzodiaze-
pines,oxazepamdoesnotundergo
CYP3A-dependentmetabolism
Diazepam
Flurazepam
Midazolam
Triazolam
Flunitrazepam
Inhaled
corticosteroids
Reported thatbeclometasonedoes
notundergoCYP3A-dependent
metabolism
Fluticasone
Mometasone
Budesonide
F. Josephson | Review-Symposium: Drug–drug interactions in the treatment of HIV infection
532 ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 268; 530–539
decreasedHDLcholesteroland increased triglyceride
levels [19].
The liability to interactwith ritonavir-boostedPIs var-
ies between statins, and interestingly, also between
PIs. With regard to elimination pathways, simvasta-
tin, lovastatin and atorvastatin are metabolized by
CYP3A. Thus, one would expect clinically relevant
DDIs between these substances and ritonavir-
boosted PI regimens. Indeed, when ritonavir and sa-
quinavir were co-administered with simvastatin, the
exposure to simvastatin acid increased 30-fold [20].
Thus, the combination of simvastatin and PIs is con-
traindicated because of the risk of rhabdomyolysis,
as is that of lovastatin and PIs by argument of anal-
ogy. Exposure to atorvastatin when co-administered
with a ritonavir-boosted PI only increases by three to
sixfold, and exposure to the activemoiety even less so
[4, 5, 20]. Although the use of atorvastatin together
with ritonavir-boosted PIs is not recommended in all
cases, titration froma lowstartingdoseunder careful
monitoring is considered an acceptable strategy in
cases of co-administration with, for example, ritona-
vir-boosted lopinavir or darunavir. The difference be-
tween the magnitudes of the increased exposure be-
tween simvastatin and atorvastatin may result from
the fact that the former is administered as a lactone
prodrug and has a lower bioavailability because of
presystemic CYP3A-mediated metabolism in the ab-
sence of a strong CYP3A inhibitor [20, 21]. This illus-
trates an important principle regarding DDIs due to
ritonavir – that the greatest-fold increase in exposure
may be seen for agents that normally have restricted
bioavailability owing to presystemic metabolism.
This principle will be further illustrated below, with
regard to the interaction between inhalational corti-
costeroidsandritonavir.
Fluvastatin is metabolized by CYP2C9, whereas pra-
vastatin and rosuvastatin do not undergo significant
CYP450-dependent metabolism [21]. Fluvastatin
and pravastatin are considered first-line possibilities
when a statin is needed in patients receiving ritona-
vir-boosted PI therapy. However, pravastatin expo-
sure was decreased by 50% when co-administered
with saquinavir and ritonavir, presumably because
of induction of metabolism [20], and recommended
doses may often not be sufficiently efficacious. Also,
contrary to expectation, when the interaction be-
tween pravastatin and ritonavir-boosted darunavir
was studied, an 81% increase in pravastatin expo-
surewasseen,anduptofivefold increaseswerenoted
in a subset of subjects [5]. To our knowledge, the
mechanism of this interaction has not been clarified,
but an effect of darunavir on the transmembrane
transport of pravastatinhasbeen suggested [22]. An-
other unexpected finding in the complex field of PI–
statinDDIswas that ritonavir-boosted lopinavir dou-
bled the exposure to rosuvastatin, and this is not
readilyexplainedonthebasis of inhibitionofmetabo-
lism [4]. However, it is considered that all statins are
substrates of the OATP1B1 transmembrane trans-
porter, which impacts their intracellular availability
[21], and lopinavir was recently shown to inhibit this
transporter at clinically relevant concentrations [23].
In summary, extrapolation of DDI data between sta-
tins and PIs has turned out to be more difficult than
initially expected, as multiple mechanisms other
thanCYP3A inhibitionare involved,andtheseappear
todifferbetweendrugs intheclass.
PI and calcium channel antagonists
There are numerous drugs in this important class,
which are used for several common conditions,
including hypertension, angina pectoris and cardiac
arrhythmias. Most, if not all, calcium channel antag-
onists are substrates for CYP3A; some are also sub-
strates forp-glycoprotein [24]. Thus, increases incal-
cium channel antagonist exposure may be expected
when co-treating with ritonavir. However, the phar-
macokinetic impact of ritonavir co-administration
appears to have been studied for relatively few cal-
cium channel blockers. Available data support the
theoretical assumption of an interaction potential;
though, the magnitude and clinical relevance of the
effectmay vary betweenagents, e.g. becauseofdiffer-
ing degrees of presystemicCYP3A-dependentmetab-
olism and ⁄or the presence of alternative metabolic
pathways. Co-administration of diltiazem or amlodi-
pine together with indinavir in combination with ri-
tonavir at a dose of 800 ⁄100 mg twice daily led to an
increase in amlodipine exposure by a median of
approximately 90%, whereas the increase in dil-
tiazem exposure wasmoremoderate [24]. In general,
if co-administeredwith ritonavir, dose titration of the
calcium channel antagonist and careful monitoring
of the response seem prudent. A useful strategy may
be to chose alternative agents to calcium channel
blockers with effects on cardiac conduction at thera-
peuticdoses, ifpossible.
Co-treatment with ritonavir and inhaled corticosteroids
In the late 1990s, two case reports of patients treated
with ritonavir developing Cushing’s syndrome, pre-
sumably because of an interaction with nasally in-
haled fluticasone, were published [25, 26]. To date,
F. Josephson | Review-Symposium: Drug–drug interactions in the treatment of HIV infection
ª 2010 The Association for the Publicationof the Journal of Internal Medicine Journal of Internal Medicine 268; 530–539 533
more than 30 cases of Cushing’s syndrome and ⁄or
secondary adrenal insufficiency because of bronchi-
ally or nasally administered fluticasone in combina-
tion with ritonavir-boosted PI therapy have been re-
ported. Some difficulties in diagnosis are noted in
these case reports. According to one, the use of nasal
fluticasone was not reported by the patient as he did
not consider this over-the-counter drug to be ‘amedi-
cine’ [26]. In other reports, the differential diagnosis
of antiretroviral therapy–associated lipodystrophy
was initially considered [27,28].
Like several other drugs in its class, such as budeso-
nide and mometasone, the inhalational steroid fluti-
casone is a CYP3A substrate [29]. Under normal cir-
cumstances, systemic exposure to fluticasone is
limited by a very high presystemic and systemic
CYP3A-mediated clearance.However, in the presence
of ritonavir 100 mg twice daily, systemic exposure to
nasally administeredfluticasone increasesmore than
350-fold, with concomitant suppression of endoge-
nous cortisol synthesis [8]. Although similar effects
might be expected from other drugs in this class, as
mentioned previously, quantitative data are lacking
concerning the interaction between ritonavir and
other agents. It is notable that the great majority of
published cases have involved fluticasone, and only
recentlywasa case of adrenal suppressionandCush-
ing’ssyndromepresumedbecauseofritonavirandbu-
desonidereported [30]. Ithasbeenspeculatedthat the
higher potency and lipophilicity, with consequent po-
tential for accumulation, might make the interaction
between fluticasone and ritonavir more significant
than between budesonide and ritonavir [29]. Also, if
the systemic bioavailability of fluticasone under nor-
malcircumstances ismorerestrictedbyCYP3A-medi-
ated metabolism, the quantitative effect of ritonavir
maybehigheronfluticasone thanonbudesonide.Be-
causeof thisuncertaintyconcerningtheDDIpotential
of other inhalational steroids that are metabolized by
CYP3A, beclometasone, which is not considered a
substrate for this enzyme, is recommended when pa-
tients treatedwitha ritonavir-boostedPIare inneedof
therapywithaninhalationalsteroid[8,29].
Antiretrovirals and acid-reducing agents
The bioavailability of some antiretrovirals is affected
by gastric pH. Consequently, various classes of acid-
reducing agents have been reported to affect the
pharmacokinetics of several different antiretrovirals,
with increased or decreased exposure as a conse-
quence [6, 31, 32]. The bioavailability of atazanavir
decreaseswith increasinggastricpH.A40-mgdoseof
omeprazole reduces the AUC of ritonavir-boosted at-
azanavir by 75% [33]. Even when the dose of ritona-
vir-boostedatazanavir is increasedfromthestandard
300 mg once daily to 400 mg, a 20-mg dose of omep-
razole reduces the AUC of atazanavir by about 30%,
and a 40-mg dose by about 60%, relative to the stan-
dard dose under normal conditions. Consequently,
concomitant use of atazanavir and proton pump
inhibitors is considered contraindicated, at least in
treatment-experienced patients who might require
higher exposure to atazanavir [6, 33]. Pharmacoki-
netic interactions with other acid-reducing agents
arealso significantandmayrequire temporal separa-
tion of doses [6, 33]. By contrast, exposure to the in-
tegrase inhibitor raltegravir is increased more than
twofold by proton pump inhibitors [32]. However, at
present, this isnot thought tobeclinically relevant.
Antiretroviral therapy and opiate substitution
As intravenous drug use is a major transmission
route forHIV,many patients treatedwith antiretrovi-
ral therapy receive concomitant opiate substitution
with methadone or buprenorphine. Methadone is a
long-acting l-opioid receptor agonist. On the basis of
in vitro studies, the elimination of methadone was
previously at least partly attributed to CYP3A. How-
ever, as a recent study showed no relation between
CYP3A activity when inhibited by ritonavir and the
impact on methadone pharmacokinetic parameters,
this has been questioned [34]. In addition tometabo-
lism, presumably involving several different drug-
metabolizing enzymes, methadone is also cleared by
renal elimination [34]. Buprenorphine, which is
administered sublingually because of extensive first-
pass metabolism, is a partial agonist of the l-opioid
receptor. It is converted to an active metabolite, nor-
buprenorphine, via CYP3A and CYP2C8, and further
metabolized through glucuronidation [35]. Thus,
both of these drugshave thepotential to interactwith
PIsandNNRTIs.
Amongst the NNRTIs, efavirenz, which is an inducer
of hepatic drug-metabolizing enzymes, approxi-
mately halved exposure to methadone and precipi-
tatedwithdrawal symptoms [1]. Clinically, the evalu-
ation of such symptoms may be complicated by the
fact that efavirenz, particularly during thefirstweeks
of therapy,maycauseCNSsymptoms that canbedif-
ficult to distinguish from symptoms of opiate with-
drawal. Although the interaction between efavirenz
andmethadonemaybemanagedbymethadonedose
adjustments, many clinicians avoid the use of efavi-
renz in such situations. The effects of nevirapine on
F. Josephson | Review-Symposium: Drug–drug interactions in the treatment of HIV infection
534 ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 268; 530–539
methadone are similar to those of efavirenz, whereas
the effects of etravirine are negligible [2, 3]. When ef-
avirenz was co-administered with buprenorphine,
themagnitude of the interaction in terms of pharma-
cokinetic effect was similar to that with methadone;
buprenorphine AUCwas decreased by 52% and nor-
buprenorphine AUC even more so. However, no pa-
tients displayed withdrawal symptoms [1]. Thus, the
pharmacokinetic ⁄pharmacodynamic relationship of
buprenorphine, a partial agonist, may be different
from that of methadone in the clinically relevant
concentration intervals. Data on the interactions
between the other NNRTIs that are licensed in the
European Union and buprenorphine appear to be
lacking.
Ritonavir at a boosting dose (100 mg twice daily) did
not significantly affect methadone exposure [36],
whereasritonavirata therapeuticdose (500 mgtwice
daily) decreased methadone exposure by 36% [8],
illustrating the dose dependence of an interaction
presumably due to hepatic enzyme induction. In
addition, the net effect of different boosted PI regi-
mensmaydependonthepotencyof the individualPIs
as enzyme inducers. Thus, lopinavir in combination
with ritonavir at the boosting dose decreasedmetha-
done AUC by an average of 28%, which was associ-
atedwithsymptomsofopiatewithdrawal [36].
DDIs and the co-treatment of HIV and tuberculosis
At leastone-thirdof thepeople livingwithHIVarealso
infectedwithMycobacteriumtuberculosisandare20–
30 times more likely to develop clinical tuberculosis
(TB) than peoplewithout HIV [37]. Inmany cases, TB
and HIV are diagnosed at the same time. In such
cases, initiating TB treatment is the first priority, but
an increasing body of evidence indicates that delay-
ing HIV treatment until after completion of TB ther-
apy (usually 6 months) increasesmortality, and par-
ticularly so in patients with substantial immune
deficiency [38]. Standard TB regimens include rifam-
picin, isoniazid and pyrazinamide with ⁄without eth-
ambutol [39]. Theuse of rifampicin, a crucial agent in
the TB regimen, may pose formidable problems with
regard to DDIs when co-treating HIV and TB. Rifam-
picinmaybe themost potent inducerofhepaticdrug-
metabolizing enzymes of all therapeutic agents in
current use [40]. As rifampicin induces CYP3A, it re-
ducesexposure tobothPIsandNNRTIs.For example,
theNNRTIs efavirenz andnevirapine are the first-line
antiretroviral drugs predominantly used in the geo-
graphical areas where HIV–TB co-infection is most
prevalent; the AUC and trough concentration (lowest
concentration during the dosinginterval, prior to the
next scheduled dose, and assumed to be the most
importantpharmacokinetic parameter for theseanti-
retrovirals) are reduced by 26% and 32%, respec-
tively, for efavirenz, and by 58% and 68%, respec-
tively, for nevirapine [1, 2]. This has led to
considerable controversy concerning the need for
dose adjustments of these agents when co-treating
with rifampicin. This issue has been complicated by
the fact that efavirenz and to some extent nevirapine
are substrates not only for CYP3A but also for the
genetically polymorphic CYP2B6 enzyme [1, 41].
Thus, exposure to efavirenz varies greatly in a popu-
lation, with patients who are homozygous for inacti-
vating mutations in CYP2B6 exhibiting several-fold
higher exposures at the recommended dose andhav-
ing an increased risk of exposure-dependent central
nervous system side effects [42]. The frequency of
inactiveCYP2B6allelesmaybeashighas50%inAfri-
can populations [43, 44], and increasing the dose in
suchpatientsmay increase side effects [45].Whereas
an increased dose of efavirenz when co-treating with
rifampicin is suggested (though not actually recom-
mended) according to European labelling [1], there is
emergingevidence tosuggest that this isnotgenerally
necessary tomaintain antiretroviral efficacy [46–48].
With nevirapine, evidence for maintained efficacy
with labelled doses when co-treating with rifampicin
is less strong [49, 50]; however, an increased dose of
nevirapine may be associated with an increased risk
ofhypersensitivity reactions, includingrashandhep-
atitis [49]. Of note, rash is an important side effect of
isoniazid, and both isoniazid and pyrazinamide may
cause drug-induced hepatitis, complicating the dif-
ferential diagnosis in case of such symptoms. There-
fore, an efavirenz-based antiretroviral regimen has
emergedasa favouredoption incasesof concomitant
TB.
Incontrast to ritonavir-boostedPIs, efavirenz andne-
virapine are both drugs with low barriers to resis-
tance. Thismeans that following virological failure on
a first-line regimen based on either of these agents,
full resistancewilloftenhavedeveloped.Thus,partic-
ularly in the geographical regions where HIV–TB co-
infection is common, an effective second-line antiret-
roviral regimenwill require a ritonavir-boosted PI. As
mentioned earlier, PI exposure is decreasedby rifam-
picin, and for pharmacokinetic reasons, unboosted
PIs are not considered to be options for co-treatment
[40]. Boosted PI regimens in combinationwith rifam-
picin, however, are not well tolerated with a high fre-
quency of hepatotoxicity [51, 52]. Thus, such combi-
nations should be avoided. The recommended
F. Josephson | Review-Symposium: Drug–drug interactions in the treatment of HIV infection
ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 268; 530–539 535
approach when treating TB in patients receiving a ri-
tonavir-boosted PI regimen is to substitute rifabutin
for rifampicin. Rifabutin induces CYP3A to a consid-
erably lower extent than rifampicin, and it does not
affect exposure to ritonavir-boosted PIs in a clinically
relevant manner. Rifabutin is considered equipotent
to rifampicin as an anti-TB agent [53]. It induces
CYP3A considerably less than rifampicin and does
not affect exposure to ritonavir-boosted PIs in a clini-
cally meaningful way. Unfortunately, however, it is
prohibitively expensive in most resource-poor set-
tings. In addition, although there is no relevant effect
of rifabutin on the pharmacokinetics of ritonavir-
boosted PIs, the latter profoundly affect the disposi-
tion of the former. Rifabutin is metabolized, mainly
bynon-CYP450mechanisms, into the activemetabo-
lite 25-O-desacetylrifabutin, which in turn is inacti-
vated by CYP3A. Under normal circumstances, this
comprisesaminorpart of the activemoiety.However,
when co-treating with a ritonavir-boosted PI, expo-
sure to rifabutin increases moderately, whereas
exposure to the active metabolite increases more
than 10-fold [5, 6]. Thus, the metabolite becomes a
considerableportionof theactivemoiety.As rifabutin
has exposure-dependent adverse effects, including
leucopenia and uveitis, a dose reduction is man-
dated. When used without significant interacting
drugs, the usual dose of rifabutin is 150 or 300 mg
oncedaily.When co-treatingwith a ritonavir-boosted
PI, the commonly recommended dose regimen is
150 mg thriceweekly or every other day,whichyields
anexposure to theactivemoiety that isstill somewhat
greater than 300 mg once daily (and considerably
higher thanwith150 mg once daily) in the absence of
interactingdrugs [5,6].
Future perspectives on CYP3A inhibition in antiviral therapy
As discussed previously, ritonavir was originally
developedtobeusedasanantiretroviralagent,acting
through inhibitionof theHIVprotease. In fact, the ini-
tial studies of the combination of ritonavir and an-
other PI were performed under the assumption that
there would be additive pharmacodynamic effects,
rather than to investigate the antiviral consequences
ofpharmacokineticboosting [54,55]. It shouldbeevi-
dent from the above that ritonavir is in fact not an
‘ideal’CYP3Ainhibitor, foranumberof reasons.First,
even at boosting doses, ritonavir has gastrointestinal
andmetabolic side effects. Secondly, the use of riton-
avir asabooster iscomplicatedby its effects onmulti-
ple other drug-metabolizing enzymes and transport
proteins. Thirdly, the fact that ritonavir has intrinsic
antiretroviral activity is not a problem when used to
boost thepharmacokinetics of anotherPI, asdrugs in
this class exhibit considerable similarity in terms of
resistance profile and, when ritonavir-boosted, have
a very high barrier to resistance. However, if ritonavir
is used at boosting doses with an agent that is not a
PI, resistance to PIs could be selected in cases of regi-
men failure, because of the presence of sub-thera-
peutic ritonavirconcentrations.
Several CYP3A inhibitors without intrinsic antiretro-
viral activity are under development; furthest along
the path is cobicistat (GS-9350). According to preli-
minary data, cobicistat is a weak inhibitor of
CYP2D6, does not inhibit CYP1A2, CYP2C9 or
CYP2C19 andhas a low tendency towards the induc-
tion of hepatic drug-metabolizing enzymes [56]. With
regard to CYP3A inhibition, cobicistat at a dose of
200 mg once daily in a multiple dose regimen pro-
duced a similar inhibition of oral midazolam clear-
anceas ritonavir100 mgoncedaily [56].Cobicistat is
entering phase III trials, and it remains to be seen
whether advantagesover ritonavir asaboosterwill be
demonstrated in terms of side effect profile. Also of
interest is the putative effect of cobicistat on trans-
membrane drug transporters; however, no data ap-
pear tohavebeenpublished todate.
Another development in the field of pharmacoki-
netic enhancement of antiviral therapy through
CYP3A inhibition is the boosting of inhibitors of the
hepatitis C virus (HCV) NS3 ⁄4A protease. Applica-
tions for marketing approval of the first-generation,
directly acting antivirals against HCV, boceprevir
and telaprevir are expected by the end of 2010. In
phase III studies, both of these drugs have been
administered thrice daily; though, twice daily
administration of telaprevir is under investigation.
Of interest, several second-generation HCV protease
inhibitors are being investigated in ritonavir-
boosted dosing regimens [57, 58]. Whilst it remains
to be seen whether this will increase therapeutic
efficacy, it does provide the pharmacokinetic prere-
quisite for once-daily dosing.
Conclusions
The aim of this review has not been to provide a com-
plete overview of pharmacokinetic DDIs in antiretro-
viral therapy,but rather to giveanoutlineof thescope
of theproblemand thecomplexity of themechanisms
involved.WhereasknowledgeofDDIs relating toanti-
retroviral agents is substantial amongst physicians
who regularly treat patients with HIV, awareness of
the problems because of pharmacoenhancement by
F. Josephson| Review-Symposium: Drug–drug interactions in the treatment of HIV infection
536 ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 268; 530–539
CYP3A inhibition, as well as of DDIs because of other
mechanisms, is lower outside the infectious disease
speciality, where physicians may only rarely see pa-
tients treated with antiretroviral therapy. Yet, as dis-
cussed, several commonly used medications, and
some drugs used to treat co-morbidities that are
highly prevalent, may need to be avoided in patients
with certain antiretroviral drug regimens or should
prompt dose adjustment of either of the co-treating
agents. Several valuable internet-based DDI data-
bases are available (e.g. http://www.hiv-druginter-
actions.org, http://www.janusinfo.se/In-English/),
some of which are available free of charge. Also, the
European summaries of product characteristics for
many of the antiretroviral drugs, available at the
European Medicines Agency home page (http://
www.ema.europa.eu),providevaluableguidance.
In addition to a general awareness of the risk ofDDIs,
some very simple general principles may be of use
when facing theproblemofapotentially clinically sig-
nificant interaction in patients receiving antiretrovi-
ral therapy. One is to consider the fact that quite of-
ten drugs within the same pharmacodynamic class
may have different pharmacokinetics and metabolic
DDI potential (e.g. statins, rifamycins and corticos-
teroids, as discussed earlier). In such cases, it may
be more rational to look for an equivalent drug that
might not interact, rather than to make a – perhaps
empirical – dose adjustment, or risk toxicities or lack
of efficacyby ignoring thepossibility of aDDI.Whena
co-treatment is crucial and there are no equally good,
noninteracting alternatives, consideration may also
be given to altering the antiretroviral regimen, unless
there is a well-established dose adjustment de-
scribed for use in the particular situation. With an
increasing number of antiretroviral agents, there
may be alternatives for many patients; for instance,
using regimens based on raltegravir, which has a
considerably lower tendency to cause DDIs than PIs
and NNRTIs, may sometimes be a way of avoiding
potentially significant interactions. Furthermore,
when considering co-medications in patients treated
with antiretroviral therapy or when facing symptoms
and signs that may be because of DDIs, it should be
remembered that several over-the-counter medi-
cines, and some natural remedies, may interact with
antiretroviral drugs, resulting in toxicities or lack of
efficacy.
Finally, it appears that the concept of pharmacoki-
neticboostingbyCYP3Ablockade ishere tostay,with
new agents being developed and its use in fields out-
side antiretroviral therapy under investigation. This
will no doubt necessitate an increased awareness of
theproblemofDDIs causedby this strategy, also out-
side the specialities prescribing CYP3A-inhibiting
pharmacoenhancers.
Conflict of interest
Noconflict of interestwasdeclared.
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