Download antiretroviral drug interactions and adverse side effects

REVIEW
ANTIRETROVIRAL DRUG INTERACTIONS
AND ADVERSE SIDE EFFECTS
—
Jennifer Cocohoba, PharmD*
ABSTRACT
The complexity of antiretroviral therapy, coupled with the lifelong duration of treatment, presents the need for extensive management of drug
interactions and adverse effects. This article
includes an extensive discussion of drug interactions involving antiretroviral agents and other
medications (eg, antibiotics, oral contraceptives,
H2 antagonists, and lipid-lowering agents) commonly used in individuals with HIV. Mechanisms
(eg, CYP enzyme induction/inhibition) by which
these interactions occur are explored and practical guidelines for dose adjustments are offered.
Also included is a review of short-term and longterm adverse effects associated with antiretroviral
therapy, along with commonly employed remedies. Practical and related counseling tips for
pharmacists are offered throughout this article in
an effort to encourage patient communication.
(Adv Stud Pharm. 2008;5(4):105-113)
*Health Sciences Assistant Clinical Professor of
Pharmacy, University of California, San Francisco, School of
Pharmacy, San Francisco, California.
Address correspondence to: Jennifer Cocohoba, PharmD,
Health Sciences Assistant Clinical Professor of Pharmacy,
University of California, San Francisco, School of Pharmacy,
C-152, Box 0622, 521 Parnassus Avenue, San Francisco,
CA 94143-0622. E-mail: [email protected].
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T
reatment of HIV requires lifelong medication therapy. In addition to taking medications to suppress the virus,
HIV-positive patients commonly receive
other agents to relieve adverse effects, to treat or prevent opportunistic infections, or to treat other chronic diseases. Often, these medications may be
prescribed by multiple providers, including cardiologists, family practitioners, and obstetrician/gynecologists. As a result of these complex health issues, health
systems, and polypharmacy, HIV-positive individuals
are at risk for adverse effects and drug interactions. In
many cases, the pharmacy is the only place where the
patient’s medication list is available in its entirety, and
the community pharmacist is often the last line of
defense in preventing the occurrence of a drug interaction. It is, therefore, critical for pharmacists to be
well informed regarding existing and emerging interactions and adverse effects of antiretroviral therapy.
DRUG-DRUG INTERACTIONS
One approach to understanding antiretroviral
drug interactions involves a review of important
mechanisms by which they may occur. Some medications may interfere with antiretroviral absorption,
resulting in subtherapeutic levels. Other agents may
produce pharmacodynamic interactions, which result
in additive toxicities or counteracting effects. Many
clinically significant interactions occur during metabolism by cytochrome P450, a family of enzymes
responsible for oxidative metabolism of a majority of
medications including non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors
(PIs), and the chemokine coreceptor antagonist maraviroc.1,2 Because NNRTIs and PIs may induce or
inhibit CYP450 enzymes (especially CYP3A4), they
may affect plasma levels of medications that are pri-
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marily metabolized by CYP3A4. Additionally, some
antiretrovirals are substrates of, or affect, p-glycoprotein and may interact with agents that are also substrates of this powerful drug efflux pump.3,4 Because it
is not possible to discuss all known and theoretical
antiretroviral drug interactions in a brief review, this
discussion will focus on clinically significant interactions (by antiretroviral class) with defined recommendations for management (Tables 1 and 2).
N UCLEOSIDE R EVERSE T RANSCRIPTASE INHIBITORS
Seven nucleoside reverse transcriptase inhibitors
(NRTIs) are currently available. Two or more of these
agents usually compose the “backbone” of an antiretroviral regimen. NRTIs are intracellular-active
molecules that have relatively few drug interactions,
because they are not metabolized by CYP enzymes.
The community pharmacist should, however, pay
close attention to regimens containing tenofovir or
Table 1. Drug-Drug Interactions Among Antiretroviral Agents
ARV Drug Class
Interactions and Recommendations
NRTIs
Didanosine
• With atazanavir: Separate 1 h before or 2 h after
• With tenofovir: Reduce didanosine dose to 250 mg daily (>60 kg) or 200 mg daily (≤60 kg)
• With tipranavir: Separate 1 h before or 2 h after
Emtricitabine with lamivudine: Do not combine
Stavudine with zidovudine: Do not combine
Tenofovir with atazanavir: Boost with ritonavir (300 mg atazanavir daily with 100 mg ritonavir daily)
NNRTIs
Efavirenz or nevirapine
With darunavir, indinavir, atazanavir, or fosamprenavir twice daily: Boost the PI with ritonavir
With fosamprenavir once daily: Fosamprenavir 1400 mg + 300 mg ritonavir daily
With lopinavir/ritonavir: Increase dose to 600/150 mg (3 tabs) twice daily
Efavirenz
With maraviroc: Increase maraviroc to 600 mg twice daily
Etravirine
With non-ritonavir boosted PIs: Do not combine
With ritonavir-boosted PIs: Use standard dose with saquinavir/ritonavir, lopinavir/ritonavir, or darunavir/ ritonavir. No data
for other boosted PIs
PIs
Ritonavir boosting
Atazanavir: 300 mg daily with 100 mg ritonavir daily
Darunavir: 600 mg twice daily with 100 mg ritonavir twice daily
Fosamprenavir: 700 mg twice daily with 100 mg ritonavir daily
Fosamprenavir: 1400 mg once daily with 200 mg ritonavir once daily
Indinavir: 800 mg twice daily with 100–200 mg ritonavir twice daily
Lopinavir: Already coformulated with ritonavir
Nelfinavir: Do not boost with ritonavir
Saquinavir: 1000 mg twice daily with 100 mg ritonavir twice daily
Tipranavir: 500 mg twice daily with 200 mg ritonavir twice daily
Maraviroc
With all PIs except tipranavir/ritonavir: Decrease maraviroc to 150 mg twice daily
ARV = antiretroviral; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor.
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Table 2. Selected NNRTI and PI Drug Interactions
Antifungal agents
NNRTIs
PIs
Voriconazole with efavirenz or nevirapine:
Not recommended due to decreased
voriconazole levels with efavirenz (no data
nevirapine). Benefit must outweigh risk if used,
monitor for antifungal efficacy
Itraconazole with darunavir, lopinavir, and tipranavir: NTE 200 mg itraconazole daily
Ketoconazole with ritonavir-boosted fosamprenavir, darunavir, lopinavir,
and tipranavir: NTE 200 mg ketoconazole
Fluconazole with tipranavir: NTE 200 mg daily
Voriconazole with ritonavir (100 mg): Use with caution, monitor
voriconazole efficacy
Antimycobacterial
agents
Rifampin with delavirdine or etravirine: Not
recommended
Clarithromycin: Clarithromycin dose should be reduced by 50% when
given with atazanavir
With efavirenz: Standard efavirenz dose if
weight ≤60 kg. Consider increasing efavirenz
dose to 800 mg if the patient weighs >60 kg
Rifabutin:
With ritonavir-boosted PIs and unboosted atazanavir: Decrease rifabutin
dose to 150 mg every other day
With nevirapine: Standard nevirapine dose
With nelfinavir or fosamprenavir: Decrease dose to 150 mg daily
Rifabutin with delavirdine: Not recommended
Rifampin: Should not be used in combination with PIs
With efavirenz: Increase rifabutin dose to
450–600 mg daily
Erectile dysfunction
agents
Sildenafil: Dose NTE 25 mg in 48 h with
delavirdine
Sildenafil: Dose NTE 25 mg in 48 h
Tadalafil: Dose NTE 10 mg in 72 h with
delavirdine
Tadalafil: Dose NTE 10 mg in 72 h
Vardenafil: Dose NTE 2.5 mg in 72 h with
delavirdine
Vardenafil: Dose NTE 2.5 mg in 72 h
Antacids: Separate atazanavir and tipranavir 1 h before or 2 h after coadministration of antacids
Acid suppressing
agents
H2 blockers:
With atazanavir: Atazanavir must be boosted with ritonavir to administer
with an H2 blocker. Dose NTE equivalent of 40 mg famotidine BID in
treatment-naïve patients taking atazanavir/ritonavir. Dose NTE equivalent
of 20 mg famotidine BID in treatment-experienced patients taking
atazanavir/ritonavir
If treatment-experienced patient is taking atazanavir, ritonavir, and tenofovir, the atazanavir should be increased to 400 mg. If BID, give 1 dose
with atazanavir/ritonavir, give second dose 12 h later
With fosamprenavir: Separate administration from fosamprenavir by 1 h
before or 2 h after; alternatively boost fosamprenavir with ritonavir to
overcome interaction
Proton pump inhibitors: Contraindicated in treatment-experienced
patients taking atazanavir/ritonavir. Dose NTE equivalent of 20 mg
omeprazole in treatment-naïve patients taking atazanavir/ritonavir
Anticonvulsants
Phenobarbital, phenytoin, and carbamazepine:
Not recommended with delavirdine (decrease
in delavirdine minimum trough concentrations)
(Continued on page 108)
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didanosine.5 Because tenofovir reduces plasma levels
of the PI atazanavir, ritonavir boosting should be used
if the 2 agents are coadministered. Tenofovir also
increases the area under the curve (AUC) of didanosine via inhibition of purine metabolism.6 This interaction requires a didanosine dose reduction to 250 mg
or 200 mg in patients weighing more than 60 kg or
less than 60 kg, respectively, as long as the creatinine
clearance is 60 mL/min or greater. Didanosine should
be given on an empty stomach (30 minutes before
eating or 2 hours after eating); therefore, separation
from medications that should be taken with food is
required. For patients with hepatitis C, didanosine
should not be administered with ribavirin, because
ribavirin may inhibit didanosine’s intracellular phos-
phorylation to its active moiety. Didanosine also
interacts with tipranavir (drug levels lowered).
N O N-NUCLEOSIDE R EVERSE T RANSCRIPTASE
INHIBITORS
The 4 currently available NNRTIs have differing
effects on cytochrome P450 enzymes, which cross all
spectrums. Delavirdine is a potent CYP3A4 inhibitor,
whereas nevirapine is a potent CYP3A4 inducer.
Efavirenz and etravirine exhibit a mixed CYP3A4
induction/inhibition pattern. In some treatmentexperienced patients, an NNRTI may be used in combination with PIs; however, efavirenz and nevirapine
tend to lower levels of PIs. Using low-dose ritonavir
boosting with darunavir, indinavir, atazanavir, or fos-
Table 2. Selected NNRTI and PI Drug Interactions (continued from page 107)
Other interactions
NNRTIs
PIs
Monitor for decreased efficacy of:
Monitor for decreased efficacy of:
Antiepileptics: With efavirenz or nevirapine
Antiepileptics: Monitor for efficacy of PI and antiepileptics (phenobarbital,
carbamazepine, and phenytoin)
Immunosuppressants: (Such as cyclosporine)
with efavirenz or nevirapine
Methadone: Titrate dose to response
Lipid-lowering “statin” agents: With efavirenz
or nevirapine
Oral contraceptives: Recommend backup method with PIs with exception
of unboosted atazanavir and indinavir.
Methadone: With efavirenz or nevirapine
Paroxetine and sertraline: May require dose increase
Oral contraceptives: Recommend back-up
method with efavirenz or nevirapine
St. John’s Wort: Contraindicated with PIs
Monitor for increased toxicity of:
Desipramine and trazodone: When used with ritonavir
Diltiazem: Decrease diltiazem dose by 50% with atazanavir
Fluticasone: Monitor for adrenal suppression and Cushing’s syndrome
Lipid-lowering agents lovastatin and simvastatin: Contraindicated with PIs
Atorvastatin: Start low, titrate slow
Pravastatin: Start low, titrate slow with darunavir
Rosuvastatin: Start low, titrate slow with lopinavir/ritonavir
Metronidazole: Avoid with tipranavir
BID = twice a day; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTE = not to exceed; PI = protease inhibitor.
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amprenavir (twice daily) is a way to overcome this
interaction. If the patient is taking a once-daily fosamprenavir regimen, an additional 100 mg of ritonavir (total 300 mg ritonavir once daily) should be
used. Similarly, lopinavir requires an extra boost if it
is combined with efavirenz or nevirapine. Because
lopinavir and ritonavir are coformulated, community
pharmacists should ensure that the lopinavir/ritonavir
dose is increased to 3 tablets, instead of the standard
2 tablets, twice daily. Because the chemokine coreceptor 5 inhibitor maraviroc is a substrate of CYP3A4, its
levels are also lowered when given with efavirenz. For
some interactions, there are no data to support dosing
modifications. For example, the newly approved
NNRTI etravirine has only been studied with a few
ritonavir-boosted PIs (ie, saquinavir, lopinavir, and
darunavir) and should, therefore, not be given with
non-ritonavir–boosted PIs.
Non-NRTIs may also interact with nonantiretroviral drug classes, including antifungals, antimycobacterials, oral contraceptives, antiepileptics, statins,
methadone, agents for erectile dysfunction, and
immunosuppressants. When a patient requires treatment for a severe fungal infection, combining
voriconazole with efavirenz may be problematic,
because the interaction may result in dramatically
reduced voriconazole levels. Although there are no
data on concomitant use of voriconazole and nevirapine, the interaction is expected to be similar, because
nevirapine is a strong CYP3A4 inducer. Coadministration of voriconazole with either NNRTI is not
recommended unless medically necessary and should
be accompanied by close monitoring of voriconazole
efficacy. Rifampin is a strong inducer of CYP3A4, but
it only lowers levels of efavirenz and nevirapine by
25% and 20% to 58%, respectively. Although
rifampin may be used safely in combination with
efavirenz and nevirapine, it should not be coadministered with etravirine or delavirdine.
Commonly used in HIV-positive patients for the
treatment of Mycobacterium avium complex,
rifabutin may interact with efavirenz, which induces
metabolism of rifabutin to result in a 35% drug level
reduction and need for a dose increase. Because
efavirenz decreases progesterone and nevirapine
decreases estrogen, an alternate method of contraception should be recommended in patients on oral contraceptives who are taking these antiretrovirals.
Antiepileptic agents (eg, phenobarbital, phenytoin,
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and carbamazepine) should not be used with delavirdine, due to a significant decrease in delavirdine minimum trough concentrations. Delavirdine raises levels
of erectile dysfunction agents, increasing the risk of
adverse effects, such as priapism and hypotension.
With the exception of delavirdine, NNRTIs may
decrease efficacy of statins, methadone, antiepileptics,
and immunosuppressants. Efficacy should be monitored and doses titrated according to effect.
PROTEASE INHIBITORS
All PIs are substrates of cytochrome P450, inhibiting CYP3A4 to varying degrees and interacting with
many of the same classes of medications that NNRTIs
interact with (ie, antifungals, antimycobacterials, contraceptives, lipid-lowering agents, antiepileptics, erectile dysfunction agents, and acid suppressing
medications).5 Of all the PIs, ritonavir is the most
potent inhibitor of CYP3A4, and this effect is exploited to inhibit the metabolism and bolster plasma levels
of other PIs (ie, ritonavir “boosting”). PIs such as
darunavir, tipranavir, and lopinavir must always be
boosted with ritonavir in order to achieve effective
plasma levels. Because maraviroc’s metabolism is
inhibited by PIs, its dose should be lowered to 150 mg
twice daily when used in combination with all PIs,
except for tipranavir/ritonavir.
Because PIs increase plasma levels of antifungals,
doses of itraconazole should not exceed 200 mg daily
when used with darunavir, lopinavir, and tipranavir.
Ketoconazole doses should not exceed 200 mg when
used with ritonavir-boosted fosamprenavir, darunavir,
lopinavir, and tipranavir. When used with tipranavir,
fluconazole doses should be limited to less than 200
mg daily. Boosting doses (100 mg) of ritonavir lowers
voriconazole levels by 39%; therefore, PI and
voriconazole combinations should be used with caution and voriconazole efficacy must be monitored
closely.
Because atazanavir strongly inhibits the metabolism of clarithromycin (used for M avium complex),
doses of the antibiotic should be reduced by 50% in
order to decrease potential for QT prolongation and
torsades de pointe. The metabolism of rifabutin is also
inhibited by PIs, requiring rifabutin dose reductions.
Rifampin is a very strong inhibitor of CYP3A4 and,
therefore, should not be used at all with PIs because it
would compromise treatment efficacy. Similarly, oral
contraceptive efficacy may be decreased by PIs, with
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the exception of unboosted atazanavir and indinavir,
for which a back-up method of contraception is not
necessary. Like delavirdine, PIs inhibit metabolism of
erectile dysfunction agents (ie, sildenafil, tadalafil,
and vardenafil); therefore, doses of these medications
should be decreased to lowest possible levels.
Metronidazole should not be coadministered with
tipranavir capsules because they contain alcohol.
Diltiazem doses should be decreased by 50% when
used with atazanavir. St. John’s Wort strongly induces
the metabolism of PIs, and its use should be avoided.7
Acid suppression therapy may be problematic for
HIV-positive patients taking PIs.5 To ensure proper
absorption, PIs such as atazanavir and tipranavir
should be separated by either 1 hour before or 2 hours
after coadministration of antacids. Histamine-receptor blockers, such as famotidine and ranitidine,
should be administered 1 hour before or 2 hours after
fosamprenavir, although boosting fosamprenavir with
ritonavir overcomes this interaction. Atazanavir must
be boosted with ritonavir in order to coadminister it
with H2 blockers, and maximum doses depend on
whether the patient is treatment-naïve or treatmentexperienced.8 Additionally, if the regimen includes
atazanavir and tenofovir, the atazanavir dose should
be increased to 400 mg daily (with 100 mg ritonavir).
Use of proton pump inhibitors with unboosted
atazanavir or in treatment-experienced patients is
contraindicated. In treatment-naïve patients receiving
ritonavir-boosted atazanavir, the equivalent of 20 mg
of omeprazole may be given 12 hours before the antiretroviral regimen.
Interactions between PIs and lipid-lowering
agents, antiepileptics, methadone, and inhaled corticosteroids warrant careful monitoring.5 Atorvastatin
levels are increased with PIs, therefore, patients
should be started on low doses and titrated carefully.
Metabolism of pravastatin is less affected by PIs, but
the statin should be titrated carefully in patients
receiving darunavir because levels could increase up to
5-fold in some patients. Pravastatin can be titrated
more aggressively in patients on saquinavir/ritonavir
because levels may paradoxically decrease up to 50%.
Because the AUC of lovastatin and simvastatin is
greatly increased when administered with PIs, the
combination may result in rhabdomyolysis and therefore, should be avoided. Complex bidirectional interactions may occur with antiepileptic agents and PIs,
which necessitates close monitoring of efficacy during
concomitant use. Because concomitant use of
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methadone and PIs may result in a seemingly paradoxical reaction mediated by non-cytochrome P450
mechanisms, symptoms of opioid withdrawal should
be monitored and methadone doses should be appropriately titrated upward to effect. The systemic
absorption of fluticasone is increased by ritonavir and
has resulted in reports of adrenal suppression and
Cushing’s syndrome. The combination should only
be used if benefits outweigh the risks. Efficacy of antidepressants, particularly sertraline and paroxetine,
may be reduced by darunavir/ritonavir, whereas
adverse effects of trazadone and desipramine may be
increased by ritonavir.
ENTRY AND INTEGRASE INHIBITORS
Maraviroc, enfuvirtide, and raltegravir have relatively few interactions for community pharmacists to
be aware of.5 Maraviroc is a substrate of CYP3A4, and
its dose should be lowered when given with CYP3A4
inhibitors, such as ritonavir, itraconazole, ketoconazole, and clarithromycin. Maraviroc’s dose should be
increased to 600 mg twice daily when given with
strong CYP3A4 inducers, such as rifampin and
antiepileptic agents. Raltegravir is not a known substrate of cytochrome P450; instead, it is primarily
metabolized by the enzyme uridine diphosphate glucuronosyltransferase (UGT1A1).9 As a result, use of
strong UGT1A1 inducers (eg, rifampin) with raltegravir is contraindicated. Raltegravir may be given
with other medications that affect UGT1A1 (eg,
atazanavir, tipranavir, phenytoin, and phenobarbital)
but efficacy and toxicity should be monitored.
ADVERSE EFFECTS OF ANTIRETROVIRALS
The community pharmacist is in a unique and
important position to counsel HIV-positive patients
on antiretroviral-related adverse effects. Because pharmacists are often the last healthcare provider patients
speak with before starting their medications, the pharmacist may serve as a “last stop” for questions. When
side effects do occur, a patient is likely to go to their
pharmacy seeking over-the-counter remedies and
advice. It is important for community pharmacists to
be aware of common antiretroviral side effects and on
how to counsel patients appropriately. Accurate information regarding adverse effects can encourage
patients to adhere with a new or existing regimen and
can promote ongoing communication with their
treating clinician.
When starting a new antiretroviral regimen, comVol. 5, No. 4
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monly experienced side effects include nausea, diarrhea, rash, and fatigue.10 These side effects usually
occur soon after starting therapy, may last 8 weeks (or
longer), and many gradually improve with time. A
patient who is not given this information may be “surprised” and discouraged to the point of nonadherence. Nausea and fatigue may occur with all classes of
antiretrovirals. Nonpharmacologic recommendations,
such as performing relaxation breathing exercises;
avoiding spicy, fatty, or large meals; eating lukewarm
food; and carrying crackers for light snacks, are useful
tips for patients suffering from nausea. Over-thecounter remedies, such as nausea pressure point wristbands or scopolamine patches, may offer minimal
relief; however, many clinicians will offer prescription
medications to relieve short-term nausea.
Fatigue generally warrants rest, but if it is extreme,
the pharmacist should be concerned regarding the
possibility of NRTI-associated lactic acidosis, especially if present with anorexia, weight loss, and nausea. The combination of rash, fever, gastrointestinal,
flu-like, and/or respiratory symptoms may be a marker for abacavir hypersensitivity reaction. If either of
these more serious adverse effects is suspected, the
patient should be encouraged to see his/her clinician
as soon as possible. Diarrhea is most commonly associated with PI therapy and may be initially treated
with over-the-counter loperamide.10 As with nausea,
clinicians may offer prescription medications (eg,
diphenoxylate/atropine or tincture of opium) to treat
diarrhea that is nonresponsive to loperamide. Patients
with low CD4 cell counts should be ruled out for
infectious causes before recommending antidiarrhea
medication.
Rash may occur in up to 30% of patients taking
NNRTIs and is also associated with PIs.10,11 The complication often begins 7 to 10 days after initiating
therapy and is marked by a diffuse bilateral maculopapular rash spreading over the trunk and extremities. In most cases, the rash is not harmful and
dissipates without treatment, though patients should
be encouraged to report the appearance of any rash to
their clinician. Over-the-counter topical corticosteroids, as well as topical and systemic antihistamines
(eg, diphenhydramine), may be used sparingly and
may offer some relief. Systemic corticosteroids should
not be recommended prophylactically, but they may
be used by the provider in patients who have developed moderate-to-severe rash. The patient should be
counseled to use mild soap, avoid harsh perfumes or
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other chemicals, take lukewarm instead of hot showers, and to protect the skin from excess sun exposure.
Patients should be told to seek medical attention if
their rash occurs on a mucous membrane (eg, eyes,
nose, mouth, and anal or vaginal areas), is painful, is
accompanied by sloughing of the skin, or constitutional symptoms. These symptoms mark a more dangerous rash that should be treated immediately.
Although nausea, diarrhea, rash, and fatigue are usually self-limiting, in some instances they are persistent, and patients may need to discuss with the
treating clinician the possibility of changing their
antiretroviral regimen.
In addition to short-term adverse effects, the
pharmacist can provide information regarding the
latest cardiovascular and metabolic toxicities, as well
as body-habitus changes associated with antiretrovirals.10 Many patients are fearful that these adverse
effects (particularly body habitus changes) will occur
soon after starting medications, but it is important
for them to understand that these changes occur over
the long-term. Such misunderstandings may serve as
a source of delays in starting therapy or may result in
nonadherence with therapy. The development of visceral fat in the trunk area, breasts, and upper back
(otherwise known as the “protease paunch” or “buffalo hump”) has been associated with PI therapy and
does not occur in all patients.12 Factors predicting
which patients will develop these complications are
not well defined, partially because of a lack of standardized definitions and measurements. If the condition occurs, there are few remedies. Low doses of
subcutaneous human growth hormone may be useful.13 Metformin and rosiglitazone have been studied
in treating body habitus changes with mixed
results.14-16 In some cases, surgical removal of visceral
fat has been attempted, although the challenge is
treating reoccurrences. Wasting of subcutaneous fat
in the limbs, cheeks, and buttocks has been found to
be associated with NRTIs. The proposed mechanism
involves NRTI inhibition of mitochondrial DNA
processing and resultant apoptosis of peripheral
adipocytes.17 Peripheral fat wasting has been more
closely associated with thymidine analogues, such as
stavudine.11 Replacement of stavudine with another
NRTI (eg, abacavir or tenofovir) has been found
to be effective in some studies, and availability of
polylactic acid filling agents may improve the
appearance.18,19
A recent study found a potential association
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between recent use (using now or stopped within the
last 6 months) of abacavir and didanosine and
myocardial infarction (MI).20 Although the overall
prevalence of MI was low in the treatment cohort
(1.6%), the relative risk was 1.9 (P = .0001) for those
taking abacavir and 1.49 (P = .003) for those taking
didanosine. The study authors could not find evidence of other MI-related factors that may have confounded the results. In previous studies, investigators
found that PI use increased the risk of MI by 16% for
every year of treatment.21 Recommendations on how
to incorporate these data into practice are not yet
clear. Patients on PIs, abacavir, or didanosine who are
at higher risk for cardiovascular events (eg,
Framingham Risk Score ≥20%) should discuss their
concerns with clinicians, thus a mutual treatment
decision can be made. Counseling should also be provided on smoking cessation, exercise, and hearthealthy diet.
Protease inhibitors may also increase levels of
triglycerides and cholesterol, and cause glucose intolerance.11 These metabolic disturbances may be a result of
HIV infection, are more likely to occur in persons with
a genetic predisposition for these conditions, and may
increase cardiovascular risk.22 Patients with dyslipidemias should be treated according to National Heart
Lung and Blood Institute guidelines (Adult Treatment
Panel III). Preferred cholesterol-lowering agents
include the statins pravastatin and atorvastatin and the
fibrates gemfibrozil and fenofibrate. Rosuvastatin is
another treatment option, although whether it will be
added as a preferred therapy in the revised HIV
Medical Association guidelines is unclear due to recent
drug interaction data suggesting that rosuvastatin levels rise about 5-fold when given in combination with
lopinavir/ritonavir.23 Use of simvastatin and lovastatin
with PIs should be avoided. If glucose intolerance
develops, standard oral diabetes medications may be
initiated. Because most diabetes medications are eliminated renally, drug interactions with antiretrovirals are
minimal. The pharmacist can offer counseling on
appropriate diet, exercise, and adherence to antiretroviral agents and medications required for associated
conditions.
CONCLUSIONS
Information regarding antiretroviral drug interactions and adverse effects evolves rapidly as new drugs
become available and additional studies are performed. A key source of important information is the
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US Department of Health and Human Services
guidelines (available at http://www.aidsinfo.nih.gov),
which are updated to reflect new recommendations
based on clinical trials.5 Pharmacists can also sign up
for the US Food and Drug Administration’s e-mail
HIV
listserv
(http://www.fda.gov/oashi/aids/
email.html), which communicates Dear Healthcare
Professional letters and updated product labeling.
These tools can help pharmacists remain as up-to-date
as possible with important new adverse effect and
drug interaction data.
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2. Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-drug
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3. Storch CH, Theile D, Lindenmaier H, et al. Comparison of
the inhibitory activity of anti-HIV drugs on P-glycoprotein.
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