Cutaneous toxicities of antiretroviral therapy for HIV

Part II. Nonnucleoside reverse transcriptase inhibitors, entry

and fusion inhibitors, integrase inhibitors, and immune
reconstitution syndrome
Camille E. Introcaso, MD,a Janet M. Hines, MD,b and Carrie L. Kovarik, MDa,b
Philadelphia, Pennsylvania
Cutaneous manifestations of antiretroviral medications for HIV are common and potentially dangerous
conditions encountered by dermatologists. Part II of this two-part series on the cutaneous effects of
antiretroviral medications for HIV will discuss the four most recent classes of medications that have been
developed and immune reconstitution syndromean important diagnostic consideration when evaluating
a dermatologic patient who is taking antiretroviral medications. ( J Am Acad Dermatol 2010;63:563-9.)
Learning objectives: After completing this learning activity, participants should be able to recognize
common and dangerous cutaneous adverse effects related to nonnucleoside reverse transcriptase inhibitors
and entry and fusion inhibitors, determine which of these toxicities need further investigation or
medication cessation, and understand the dermatologic manifestations of immune reconstitution syndrome
and their importance in the differential diagnosis of a drug reaction in HIV-positive patients.
Key words: antiretroviral medications; cutaneous; drug eruption; HIV; immune reconstitution syndrome;
toxicities.

NONNUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
Key points
d

Nonnucleoside reverse transcriptase inhibitors are the most frequent class of antiretrovirals to cause morbilliform exanthems
Morbilliform eruptions related to nevirapine
may become severe and be associated with
systemic hypersensitivity reactions; therefore, the introduction of nevirapine at a low

From the Department of Dermatologya and the Division of

Infectious Diseases,b Department of Internal Medicine, University of Pennsylvania, Philadelphia.
Funding sources: None.
Dr Hines has been on the advisory board for Abbot, Boehringer
Ingelheim, Bristol Meyers, Gilead, and GlaxoSmithKline, and has
been a speaker for Boehringer Ingelheim, Bristol Meyer, and
GlaxoSmithKline. Drs Introcaso and Kovarik and the editors, planners, and peer reviewers have no relevant financial relationships.
Reprint requests: Carrie L. Kovarik, MD, Departments of
Dermatology and Internal Medicine, Division of Infectious
Disease, University of Pennsylvania School of Medicine, 2nd fl,
Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104. E-mail:
carrie.kovarik@uphs.upenn.edu.
0190-9622/$36.00
2010 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2010.02.059

dose with escalation over a 2-week period is

recommended
Nonnucleoside reverse transcriptase inhibitors
(NNRTIs) were the third class of antiretroviral medications to be developed. These medications bind at
a site distant to the active site of the HIV reverse
transcriptase enzyme and prevent conversion of RNA
to DNA (Fig 1). Currently, there are four drugs in the
NNRTI class that are approved by the US Food and
Drug Administration (FDA) for combination treatment of HIV. At least one other NNRTI, rilpivirine, is
currently undergoing clinical trials. In general, medications in this class are known to cause a high
incidence of morbilliform eruptions during the first
month of therapy. Many of these eruptions resolve
despite continuation of therapy; however, a patient
must be closely observed during an eruption because StevenseJohnson syndrome (SJS) and systemic hypersensitivity syndromes have also been
reported with NNRTIs. One report has associated a
previous reaction to sulfa drugs with a higher likelihood of developing a morbilliform eruption when
exposed to NNRTIs,1 but this point remains controversial and is not the experience of most clinicians.
However, because of the possibility of a morbilliform
eruption occurring with either a sulfa drug or an
NNRTI, the simultaneous initiation of both classes
563

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OCTOBER 2010

can cause difficulty in isolating the single cause of the

eruption.

Although oral glucocorticoids and cetirizine have

been shown to be ineffective in preventing
nevirapine-associated hypersensitivity, an escalating
dose scale for nevirapine has been established that
Nevirapine
decreases the risk of systemic hypersensitivity reacApproved by the FDA for HIV treatment in 1996,
tion.18,19 It is now recommended that adult doses of
nevirapine was the first drug developed representing
nevirapine are started at 200 mg per day for 2 weeks,
the NNRTI class. The most common and some of the
and that the dose is only
most potentially dangerous
increased to the standard
side effects of nevirapine are
CAPSULE SUMMARY
400 mg per day if there is
skin toxicities; a morbilliform
no rash (or if a rash is not
eruption has been described
Multiple new classes of antiretroviral
worsening) at the end of the
in 13% to 19% of patients and
medications have been developed in the
2-week trial period.19 As
in as high as 28% in some
last 2 decades.
2,3
mentioned, the development
populations. In addition, a
Nonnucleoside reverse transcriptase
of fever in the presence of a
systemic hypersensitivity reinhibitors, entry and fusion inhibitors,
rash during the first several
action or severe rash has
and integrase inhibitors have common
weeks of nevirapine treatbeen seen in as many as 8%
and potentially serious skin
ment should prompt disconof patients.4 Nevirapine has a
manifestations.
tinuation of the drug and
black box warning because
indicate monitoring for sysof potentially fatal hepatitis,
Immune reconstitution syndrome is an
temic hypersensitivity.
and one half of the patients
inflammatory condition that may occur
who develop hepatitis do so
when HIV patients are started on
Delavirdine
in the setting of a rash and
antiretroviral medications, and must be
Delavirdine
was
apother signs of a hypersensiconsidered in the differential diagnosis
proved
for
combination
thertivity reaction.5 Liver enof a patient with a skin complaint who is
apy of HIV in 1997; however,
zymes must be checked in
taking antiretroviral therapy.
because of its lower efficacy
any patient on nevirapine
than other medications and
who develops skin findings,
its dosing schedule of three times per day, it is not
and if a morbilliform exanthem occurs in the setting
indicated for initial treatment. It also has a complex
of a fever, hepatitis, or other systemic symptoms,
set of drug interactions related to its metabolism by
nevirapine must be discontinued immediately.
the cytochrome P450 system, and for all of these
Many studies have investigated the possible risk
reasons delavirdine is rarely used in clinical practice
factors for development and treatment of nevirapineat this time. In clinical trials, between 18% and 50% of
associated exanthems and hypersensitivity reactions.
patients taking delavirdine were reported to have a
There is evidence to suggest that patients with higher
diffuse, pruritic rash, usually in the first 2 months of
CD4 cell counts, including patients using nevirapine
therapy.20-22 Therapies included topical and oral
as postexposure prophylaxis, have a higher risk of
steroids and antihistamines, and a low percentage
systemic hypersensitivity reaction, and therefore
of patients required treatment cessation. Oral ulcers
nevirapine is not recommended as part of postexhave also been reported to be associated with
posure prophylaxis regimens.6-10 Some studies also
delavirdine.13
show an association between female sex and development of a morbilliform eruption without a sysEfavirenz
temic hypersensitivity reaction.3,8,11,12
Other adverse effects of nevirapine have included
Efavirenz is an NNRTI that is currently recomcase reports of oral ulcers (Fig 2) and cases of acute
mended as part of initial therapy for treatment nave
generalized exanthematous pustulosis, both of
patients, and is one of the medications that makes up
which resolved with discontinuation of nevirapine,
a triple drug combination pill (with tenofovir and
and a patient with the development of a white
emtricitabine) that allows for an only one-pill, once
plaque on the buccal mucosa associated with xeroper day dosing regimen. In the mid-2000s, efavirenz
stomia and a burning sensation that resolved followbecame the first-line backbone of treatment over
ing cessation of nevirapine.13-15 SJS has also been
protease inhibitors for adults and children and was a
reported in association with nevirapine, and nevirpreferred component of postexposure prophylaxis
apine is one of the more common causes of SJS in the
regimens, making it one of the most commonly
developing world, where nevirapine is frequently
encountered antiretroviral drugs.23-25 Common tox2,4,16,17
(Fig 3).
icities include neuropsychiatric effects, such as
used
d

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VOLUME 63, NUMBER 4

Fig 1. 1, Entry and fusion inhibitors prevent HIV genetic

material from entering the cell. 2, Nucleoside reverse
transcriptase inhibitors competitively inhibit the HIV reverse transcriptase enzyme. 3, Nonnucleoside reverse
transcriptase inhibitors prevent conversion of HIV RNA
to DNA. 4, Integrase inhibitors prevent the entry of the
proviral DNA into the host cells genome. 5, Protease
inhibitors prevent HIV proteases from cleaving viral precursors within the infected CD41 cell, which is necessary
for HIV to spread from one cell to the next.

Fig 2. Oral ulcers and facial rash in a pediatric patient

taking nevirapine.

nightmares and dizziness, and morbilliform exanthems and lipodystrophy have been recently described. In clinical trials, between 5% and 34% of
patients on regimens including efavirenz developed
any type of rash, and generally less than 1% of
patients experienced a rash grade 3 or 4 on the World
Health Organization toxicity scale or SJS.3, 26-29
Rashes tended to start in the first 1 to 3 weeks and
resolve within the next 2 to 3 weeks without requiring cessation of medication.29 Because of its high
level of efficacy and ease of dosing, efavirenz is a
particularly important medication in the treatment

Fig 3. StevenseJohnson syndrome in a patient taking

nevirapine.

of HIV, and the medication should not be stopped

based on a morbilliform eruption alone.
A retrospective review reported that 12.6% of patients
with a rash of any severity during nevirapine therapy
also developed a rash during efavirenz therapy.30
Nevirapine-associated hepatitis was not reported to
recur with efavirenz treatment.30 Therefore, a history
of nevirapine-associated rash is not a contraindication for treatment with efavirenz, although caution
must be undertaken. However, if a patient has a
cutaneous reaction to efavirenz, 50% of those patients
have been reported to go on to develop a rash when
treated with nevirapine. If the therapeutic goal is
cessation of the rash alone, current evidence suggests
that it is more prudent to continue efavirenz, provide
supportive care, such as topical steroids and other
antipruritics, monitor for systemic signs, and wait for
resolution than to switch to nevirapine.30
Etravirine
In early 2008, etravirine became the first drug
representing the second generation of NNRTIs to be
approved by the FDA for use in adults with therapyresistant HIV-1. Etravirine is an important and unique
medication that has been shown to be effective in
reducing HIV viral load in patients who are resistant to
other NNRTIs. As with other NNRTIs, cutaneous
adverse effects are common, although not usually
severe. In a phase IIb and two phase III trials, the
incidence of any rash was between 14% and 20% in
patients treated with etravirine plus a background
regimen compared to 7.5% to 10% in patients on a
background regimen alone.31-33 A broad definition of
rash was used, and included urticaria, morbilliform

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OCTOBER 2010

exanthems, erythema, pustular eruptions, and dermatitis.33 In each of these three trials, rashes generally
appeared within the first 1 to 3 weeks of treatment and
resolved despite continued treatment over the following 2 weeks.31-33 Between 2% and 3.1% of patients
discontinued therapy because of the rash, and there
were no rashes that were severe enough to be a grade
4 according to the World Health Organization toxicity
scale. Less than 0.1% of patients experienced a rash
that was more specifically described as SJS, erythema
multiforme, or that was part of a systemic hypersensitivity reaction.34 In addition, less than 2% of patients
experienced other cutaneous effects, including gynecomastia, dry skin, hyperhidrosis, or lipohypertrophy.34 As has been seen with the NNRTIs nevirapine
and efavirenz, rash occurred more frequently in
women than in menalthough unlike nevirapine,
there was no correlation between occurrence of rash
and baseline CD4 counts.9,32,33 Further information
on the cutaneous effects of etravirine will likely
become available as experience with this novel
NNRTI grows.

ENTRY AND FUSION INHIBITORS

Key point
d

The fusion inhibitor enfuvirtide requires

subcutaneous administration and has a very
high incidence of injection site reactions

In order to infect a cell, the HIV virion must first

bind to the cell and enter it. This interaction occurs in
a well-understood sequence of protein interactions
between HIV surface proteins and specific CD4 cell
receptors (Fig 1). There are currently two approved
entry inhibitors (EIs) in the United States, with many
more in active development.
Enfuvirtide
Enfuvirtide binds to the HIV surface protein gp41
and prevents the virion from interacting with and
fusing to the CD4 cell membrane. Because of its
mechanism of action, it only has efficacy against
HIV-1, which accounts for the vast majority of HIV
disease in the Western hemisphere. It is currently used
in salvage regimens only because of its high cost and
the need to administer it subcutaneously; however, for
patients with significant resistance to other classes of
antiretrovirals, it represents an important, novel medication and possibly a bridge to a future, more convenient, therapy.
In two large phase III clinical trials, enfuvirtide
had between a 68% to 98% incidence of injection site
reactions, ranging from bruising, induration, and
erythema to nodules, cysts, and localized sclerosis.35,36 Approximately 3% of patients discontinued

the medication because of these reactions.

Generalized rash and hypersensitivity reaction has
also been reported in a significantly lower number of
patients.37-39 One study examined biopsy specimens
from injection sites of seven patients and examined
hematoxylineeosin-stained sections as well as sections for immunoperoxidase stains for inflammatory
cells and enfuvirtide itself. All patientsregardless of
the type or presence of a clinical reactionwere
found to have inflammation and deposition of
enfuvirtide. The inflammation pattern was similar
to that seen in granuloma annulare or interstitial
granulomatous drug reaction.40
Maraviroc
Maraviroc binds to the CCR5 chemokine receptor
on human CD41 cells and blocks the interaction
between the HIV-1 virion and CCR5, preventing entry
of the virion into the cell.41 Like enfuvirtide, maraviroc is specific for HIV-1, and in addition is specific
only for virus that uses CCR5 as its coreceptor. Some
types of virus are able to use a different coreceptor,
CXCR4; therefore, pretreatment testing is necessary
to determine if the tropism of the virus is for CCR5,
CXCR4, or both. Maraviroc was approved for oral
administration in combination therapy for patients
with CCR5-tropic HIV-1 by the FDA in 2007. In the
MOTIVATE 1 and 2 preclinical trials that compared an
optimized background regiment plus placebo to
background regimen plus maraviroc, rash without
further definition was seen in 16.5% of patients
treated with maraviroc versus 10.7% on background
regimens plus placebo.41 As clinical experience with
this new medication grows, it is likely that its cutaneous toxicities will be further characterized.

INTEGRASE INHIBITORS
Key point
d

The integrase inhibitor raltegravir was recently approved by the FDA, and initial studies do not report significant cutaneous side
effects

HIV-1 integrase protein catalyzes the entry of the

proviral DNA into the host cells genome (Fig 1).
Raltegravir represents the only currently approved
drug in the category of integrase inhibitors (IIs), and
it was approved for treatment in combination of
drug-resistant HIV-1 by the United States FDA in
2007.42 In the most current publication of the ongoing BENCHMRK studies monitoring groups of patients on raltegravir plus background therapy versus
placebo plus background therapy, cutaneous toxicities were not mentioned in the list of adverse events
occurring in 2% of patients or more.43 Again, as

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VOLUME 63, NUMBER 4

experience grows, it is likely that cutaneous adverse

events will be recognized.

IMMUNE RECONSTITUTION SYNDROME

Key points
d

Immune reconstitution syndrome occurs

during the initiation of antiretroviral therapy and must be distinguished from a drug
reaction
Cutaneous manifestations are common and
include appearance or worsening of human
papillomavirus, varicella-zoster virus, mycobacterial, and fungal infections

While it is not a cutaneous toxicity relating to a

specific antiretroviral medication, immune reconstitution syndrome (IRS), or immune reconstitution
inflammatory syndrome, deserves mention here,
given its frequent skin manifestations and its developing during the initiation of antiretroviral therapy.
IRS has a wide spectrum of clinical manifestations
and occurs as the patient recovers the ability to
mount an inflammatory response. Suggested causes
have included deregulated, rapid increases in
antigen-specific inflammatory cells that act to unmask previously subclinical infections or inflammatory conditions.44,45 This inflammatory response may
be to infectious agents, such as mycobacteria, opportunistic fungi, or viruses present at the time of
antiretroviral medication institution, and results in a
paradoxical clinical worsening of the patients status
despite the increase in CD4 cell counts.
In an ethnically diverse retrospective cohort, up to
25% of patients started on antiretroviral therapy will
experience some manifestations of IRS, the majority
of them cutaneous.44 The highest risk patients seem to
be those who begin antiretroviral therapy with a low
nadir (\200) of CD4 cells and those with subclinical
opportunistic or other infections at the time of
antiretroviral therapy initiation. Differentiation from
a drug reaction, worsening HIV infection, or development of a new infection can be challenging.
A diagnosis of IRS requires the introduction of
antiretroviral therapy in an HIV-infected patient, a
significant decrease in the HIV RNA level or increase
in the CD4 cell count, symptoms or signs consistent
with an infectious or inflammatory condition, and the
exclusion of other causes.46
The most common types of infections seen as part
of IRS are ones that frequently affect the skin, including
human papillomavirus in the form of genital, flat, or
common warts, reactivation of the varicella-zoster
virus or cytomegalovirus, cutaneous mycobacterial
infection, or molluscum contagiosum.47-54 Kaposi sarcoma and fungal and parasitic infections, specifically

leishmaniasis, have also been reported as part of

IRS.55-59 In addition, inflammatory dermatoses without
an infectious component have been seen to develop or
worsen after institution of antiretroviral therapy.
Tumid lupus, sarcoidosis, and even inflammatory
reactions to tattoos have been reported.60-62 At this
time, no specific prophylaxis against IRS is recommended for all patients because of the variety and
unpredictability of the manifestations of IRS. In most
cases, it is crucial that antiretroviral therapy be continued for viral control, and IRS is most effectively treated
by identifying and treating any underlying infection.
Although it heralds the possibility of immune
recovery from HIV, IRS can be dangerous and even
fatal if the infection it unmasks is systemic.59,63
Dermatologists can play an important role in diagnosing systemic infections based on skin manifestations,
and in instituting appropriate antiinfective and supportive therapy through systemic or topical steroids,
antipruritics, immune modulators, and pain control.

CONCLUSION
Patients taking antiretroviral medications have
frequent and sometimes dangerous cutaneous adverse effects. Knowledge of these medications and
an understanding of their cutaneous toxicities allow
dermatologists to differentiate drug reactions from
infectious, neoplastic, or inflammatory disease, all of
which are common in HIV patients, and to manage
these toxicities in an effective way without limiting
patient options for therapy.
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Answers to CME examination

Identification No. 810120
October 2010 issue of the Journal of the American Academy of Dermatology.

Questions 1-4, Introcaso CE, Hines JM, Kovarik CL. J Am Acad Dermatol 2010;63:563-9.

1. e
2. c

3. d
4. e