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of the Journal of Internal Medicine Journal of Internal Medicine 268; 530\u2013539 533
more than 30 cases of Cushing\u2019s syndrome and \u2044or
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 \u2018amedi-
cine\u2019 [26]. In other reports, the differential diagnosis
of antiretroviral therapy\u2013associated 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-
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
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
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
adjustments, many clinicians avoid the use of efavi-
renz in such situations. The effects of nevirapine on
F. Josephson | Review-Symposium: Drug\u2013drug 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\u2013539
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 \u2044pharmacodynamic 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
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
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 \u2044without 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\u2013TB co-infection is most
prevalent; the AUC and trough concentration (lowest
concentration during the dosing