CLINICAL THERAPEUTICS/VOL. 23, NO.

10,200l

Hypersensitivity Reactions During Therapy with the

Nucleoside Reverse Transcriptase Inhibitor Abacavir
Seth Hetherington, MD, Sue McGuirk, PhD,2 Gwendolyn Powell, MD,
Amy Cutrell, MS,l Odin Naderer, PharmD, Bill Spreen, PharmD,
Steve Lufon, MSc, Gill Pearce, PhD,2 and Helen Steel, MD2
GlaxoSmithKline, Research Triangle Park, North Carolina, and 2GlaxoSmithKline,
Greenford, Middlesex, England

ABSTRACT
Background: Hypersensitivity
reactions consist of a variable group of clinical findings
and have been described for a wide variety of chemical compounds.
Objective: This review characterizes the clinical profile of hypersensitivity
to the nucleoside reverse transcriptase inhibitor abacavir sulfate.
Methods: We performed a retrospective medical review of pooled adverse events data
from -200,000 patients who received abacavir in clinical trials, through expanded-access
programs, or by prescription from 1996 through 2000. Screened cases of hypersensitivity
were classified as either definitive or probable. Definitive cases were identified when initial symptoms resolved on interruption of abacavir therapy and returned on reintroduction
of abacavir therapy.
Results: A total of 1803 cases were identified, 1302 in the 30,595 patients participating in clinical trials or the expanded-access
program and 501 in patients from the postmarketing experience. On review, 176 (9.8%) of these cases were considered definitive
and the remainder probable. Based on the 1302 cases identified in clinical trials or the
expanded-access
program, the calculated incidence of hypersensitivity
was 4.3%. Symptoms reported in 220% of cases of this multiorgan reaction included fever, rash, malaise/
fatigue, and gastrointestinal
symptoms such as nausea, vomiting, and diarrhea, among
others. Respiratory symptoms occurred in 30% of cases and included dyspnea (12%),
cough (lo%), and pharyngitis (6%). In 90% of cases, hypersensitivity
reactions occurred
within the first 6 weeks after initiation of abacavir (median time, 1 1 days); after an initial reaction, rechallenge with abacavir resulted in the reappearance of symptoms within
hours of reexposure. Hypotension was present in 25% of these rechallenge reactions.
Among patients who received abacavir in clinical trials, the mortality rate was 0.03%
(3 per 10,000 patients).
Presented in part at the 7th Conference on Retroviruses and Opportunistic Infectiona; January 31LFebruary

2,

2000; San Francisco, California.

Accepted for publication
August 7, 2001.
Printed in the USA. Reproduction in whole or part is not permitted.
0149.2YlX/Ol/$lY.W

1603

CLINICAL

Conclusions:
Hypersensitivity
to abacavir is an idiosyncratic reaction and a distinct clinical syndrome characterized predominantly
by systemic involvement.
It
can be expected to appear as a treatmentlimiting event in -5% of patients. The appearance of clinical symptoms consistent
with this syndrome mandates immediate
discontinuation
of abacavir. Hypersensitivity to abacavir is an absolute contraindication to subsequent treatment with
any formulation that includes this agent.
Key words: nucleoside
reverse transcriptase inhibitor, abacavir, drug hypersensitivity, adverse effects. (C/in Ther: 200 I ;
23:1603-1614)

INTRODUCTION
Abacavir sulfate is a nucleoside reverse
transcriptase
inhibitor (NRTI) approved
for the treatment of HIV-I infection..* In
2 Phase 11 dose-ranging clinical trials of
abacavir,, 5 of 139 (3.6%) patients experienced an unexpected reaction characterized by combinations of symptoms that
included fever, nausea, vomiting, and skin
rash. Symptoms resolved on discontinuation of abacavir. When abacavir was reintroduced in these patients, symptoms returned within hours. Among 25 clinical
protocols in the clinical development of
abacavir, 3.7% (range, 0%-14%) of patients who received abacavir experienced
this reaction in varying degrees of severity.s The combination of skin rash, fever,
and gastrointestinal
(GI) symptoms seen
in this reaction to abacavir was clinically
consistent with an idiosyncratic hypersensitivity reaction.6
Idiosyncratic hypersensitivity
reactions
are so named because the underlying
mechanisms are unknown. Reactions of
this type are infrequent or rare, appearing

1604

THERAPEUTICS

in 1 in 1000 to I in 10,000 treated patients.

and are thus not usually identified until
later in the drug-development
process
when larger numbers of patients have received the drug. In addition, these reactions are relatively dose independent: reduction of the administered dose (within
the range of pharmacologic activity) does
not prevent or avoid the reaction.-* Idiosyncratic hypersensitivity
reactions account for 3% to 25% of all adverse drug
reactions reported. These reactions present clinical difficulties because they are
potentially
fatal and may be indistinguishable from other disease processes.
Although the mechanisms for these reactions are not well understood, evidence
suggests that genetic, immunologic.
and
metabolic factors are involved.6m
We retrospectively reviewed cases consistent with a possible hypersensitivity reaction to abacavir that were reported to
GlaxoSmithKline
in clinical trials and
postmarketing
reports. This article describes cases identified in an estimated
200,000 patients who received abacavir in
clinical trials, through expanded-access
programs, or by prescription from 1996
through 2000.

MATERIALS

AND METHODS

Data Sources
We reviewed studies in which abacavir
was administered
alone or as part of a
multiple-drug
regimen for the treatment
of HIV- I infection through December 3 I,
2000. The studies included multiple-dose
Phase II studies (CNA2001, 2002, 2003,
2004); randomized, controlled Phase 111
studies (CNA3001,
3002, 3003, 3005,
3006); international expanded-access programs; and studies conducted by individ-

KHETHERINGTONETAL

ual investigators or collaborative groups.

To maximize reporting of cases that occurred as part of the expanded-access program, after March 1997 investigators were
instructed to report all hypersensitivity reactions to abacavir as serious adverse
events using case-report forms provided
by Glaxo Wellcome. Reports of hypersensitivity reactions in patients who received a prescription
for abacavir were
also obtained. These reports were included
in the Glaxo Wellcome Worldwide Product
Safety and Pharmacovigilance
adverseevent database through postmarketing surveillance programs.
Data from clinical trials were monitored and quality-assured
according to
standards established by GlaxoSmithKline
in compliance with good clinical practices
and the International Conference on Harmonisation regulations (2 1 CFR Part 3 12,
ICH [E6]). Information available for individual cases was reviewed as outlined later
in the article. By their nature, data from
the expanded-access
programs and postmarketing reports could not be as rigorously assessed. Data sources included serious adverse event report forms received
by Glaxo Wellcome from study investigators during the conduct of clinical trials
and, for spontaneously
reported cases
from sources other than clinical trials, data
from the MedWatch reporting program
(FDA form 3500A). Physicians
from
Glaxo Wellcome
Worldwide
Product
Safety and Pharmacovigilance,
as well as
from Glaxo Wellcome HIV Clinical Development, reviewed all data.

Identification

of Cases

We selected for medical review any

case with documented reports of either of
the following: (1) hypersensitivity,
ana-

phylactic reaction, allergic reaction, or

drug allergy; or (2) 22 adverse events that
included skin rash, fever, constitutional
symptoms (lethargy, malaise, myalgia,
arthralgia, or general ill feeling), GI symptoms (nausea, vomiting, diarrhea, or abdominal pain), or respiratory symptoms
(dyspnea, pharyngitis, or cough). Selected
cases were excluded from further analysis
if rechallenge with abacavir was negative,
abacavir was continued
and symptoms
resolved, or an alternative cause of the
symptoms was definitively diagnosed (eg,
culture-proven
sepsis). Additional information was requested as needed from the
physician originally reporting the event.
A case of hypersensitivity
was considered definitive when a positive rechallenge with abacavir was documented
based on the following sequence of events:
(1) the patient experienced symptoms of
hypersensitivity
that led to discontinuation of abacavir; (2) the symptoms resolved thereafter; and (3) reintroduction
of abacavir (rechallenge) resulted in the
return of symptoms
within hours. All
cases meeting,this
set of conditions are
hereafter referred to as rechallenge cases.
Because of potential fatal outcomes, the
reintroduction of abacavir was contraindicated in clinical trials and after regulatory
approval of abacavir.
Cases were considered probable hypersensitivity reactions if (1) the clinical presentation was consistent with that in the
definitive cases, but without rechallenge,
or (2) the reporting physician recorded the
case as a hypersensitivity or allergic reaction to abacavir. Given that patients often
received multiple medications with the potential for multiple side effects, some cases
may have been incorrectly ascribed to a
hypersensitivity reaction to abacavir. Nevertheless, if, on review, a case was consid-

1605

CLINICAL

ered compatible with hypersensitivity

to
abacavir, it was included in the analysis.
All the analyses described herein include
the aggregate of definitive and probable
cases, unless otherwise specified.
The cases of hypersensitivity
selected
from clinical trials are hereafter referred
to as clinical trial cases, and the cases involving prescription abacavir are referred
to as postmarketing cases.

Data Analysis
The incidence of hypersensitivity
reactions was calculated based on the number
of cases, definitive and probable, that occurred in all patients who received abacavir while enrolled in clinical trials, including the expanded-access
program.
Clinical and laboratory findings were analyzed to describe the reaction in all identified cases of abacavir hypersensitivity
from clinical trials, expanded-access programs, and postmarketing experience. In
the definitive cases, we compared symptoms observed during the initial presentation and during rechallenge.
Mortality
rates were estimated from the number of
cases of hypersensitivity
reported in clinical trials. To be considered related to hypersensitivity, a fatal event had only to be
preceded by a clinical syndrome consistent with hypersensitivity
in a patient receiving abacavir, irrespective of the reported cause of death.

RESULTS
Incidence

A total of 1803 cases of hypersensitivity were identified using the case definition. These included 1302 cases in the
30,595 patients (incidence, 4.3%) partici-

1606

THERAPEUTICS

pating in clinical trials or the expandedaccess program and 501 patients from the
postmarketing
experience.
Among all
identified cases, I76 (9.8%) were considered definitive by virtue of a positive
rechallenge.

Time to Onset
The time from initiation of abacavir
to the onset of symptoms of a hypersensitivity reaction was available for 1682
of the 1803 (93.3%) cases. The figure
presents the frequency distribution
by
time to onset (up to 42 days) for 1514
cases; 168 cases started after 42 days.
The median time to onset was 11 days. In
90% of cases, symptoms of hypersensitivity to abacavir began within 6 weeks of
starting therapy. Overall, 1594 (94.7%)
cases started within 3 months after the
initiation of abacavir treatment; 88 (5.2%)
occurred at least I2 weeks after initiation
of treatment.

Initial Presentation
Symptoms observed during the initial
presentation
were similar
in clinical
trial cases and postmarketing cases. The
4 most frequently
reported symptoms
associated with the initial presentation
of abacavir hypersensitivity
were fever,
rash, malaise/fatigue, and nausea/vomiting
(Table I). Other less commonly reported
signs and symptoms included myalgia or
arthralgia, headache, diarrhea, pruritus,
and respiratory symptoms such as dyspnea. cough, or pharyngitis.
Importantly.
92% of cases included fever and/or rash,
and 66% had both fever and rash, but 34%
did not have rash. Thus, no single symptom or combination of symptoms was consistently present.

S. HETHERINGTON ET AL.

80
60

11

13

15

17

19 21

23

25

27

29

31 33

35

37

39

41

Time to Onset (d)

Analysis of the time to onset of cases of abacavir hypersensitivity.

Data are
shown for 15 14 cases from clinical trials and the postmarketing experience with
times to onset of up to 42 days; in an additional 289 cases, the time to onset was
unknown (n = 121) or >42 days (n = 168).

Rechallenge

Presentation

The symptoms observed after rechallenge were compared with those observed
during the initial presentation
in 128 of
the 176 (72.7%) definitive cases. Overall,
the types and rank frequencies of symptoms were similar (Table II). However,
fever (P = 0.014), hypotension
(P =
O.OOl), edema (P = 0.040), and tachycardia (P = 0.001) were reported significantly
more often on rechallenge than on initial
presentation. In addition, the rechallenge
reaction was more severe than the initial
reaction, as indicated by the more frequent presence of hypotension and tachycardia. Reasons for restarting abacavir

(leading to the rechallenge reaction) were

varied, including
uninformed
or unexplained patient decision and ascription of
the original symptoms to either an infectious disease or a reaction to a medication
other than abacavir.

Respiratory

Symptoms

Among the 1803 cases of hypersensitivity, 538 (29.8%) involved a respiratory

tract symptom during the initial or rechallenge presentation.
Reported respiratory
symptoms included dyspnea (12%), cough
(1 O%), and pharyngitis (6%) (Table I). In
a more detailed analysis of 128 rechallenge cases reported through December

1607

CLINICAL THERAPEUTICS

Table 1. Number and frequency of specific symptoms reported in 2.5% of

1803 cases of hypersensitivity to
abacavir
from clinical
trials,
expanded-access
programs, and
postmarketing reports from 1996
through 2000.
Symptom
Fever
Rash
Malaise/fatigue
Nausea/vomiting
Myalgia or arthralgia
Headache
Diarrhea
Pruritus
Abdominal pain
Dyspnea
Cough
Edema
Hypotension
Pharyngitis
Flu-like illness
Mouth/lip lesions or
inflammation

No. of Cases (70)

141 I
I 184
833
822
492
416
394
348
227
213
I85
142
I31
I08
106

(78)
(66)
(46)
(46)
(27)
(23)
(22)
(19)
(13)
(12)
(IO)
(8)
(7)
(6)
(6)

97 (5)

3 1, 2000, 27 (2 1%) had a respiratory tract

symptom (Table II). The most common
respiratory symptoms on rechallenge were
tachypnea
(14%), respiratory
distress
(5%), and pharyngitis (4%). Cough and
pneumonia were recorded in few patients.
Eleven of the 19 (57.9%) patients who died
had respiratory symptoms at the time of
initial presentation.

Physical Findings
The true frequency of any physical finding is uncertain, because patients may have
discontinued medication without being examined by a physician. The rash observed

160X

was often described as maculopapular or

urticarial, and nearly all such rashes were
judged mild or moderate in severity.
Vesiculobullous
lesions were reported in
patients receiving concurrent medications
known to cause Stevens-Johnson
syndrome. Lymphadenopathy was reported in
4% of patients. Notably, bronchospasm
was reported in only 3 patients.

Laboratory Abnormalities
Procedures for the evaluation and management of patients presenting with symptoms of a hypersensitivity
reaction were
not dictated by the protocols of any of the
clinical trials or the expanded-access program, beyond the guidance to stop abacavir and avoid rechallenge. Therefore, the
true incidence of laboratory abnormalities
in association with abacavir hypersensitivity is unknown. Cases in which laboratory
values were obtained probably represent
more severe cases. Among the laboratory
findings recorded, lymphopenia, Ieukopenia, and thrombocytopenia were noted. Increases in measures of liver function were
recorded in 14% of cases. Elevations in
creatine phosphokinase and serum creatinine levels were occasionally observed.
Chest radiographs were obtained in 98
cases, and the findings were normal in 64
(65.3%). Abnormalities were described as
interstitial or bilateral (n = l5), lobar (n = 5),
pulmonary edema (n = 2), granulonodular/
micronodular (n = 2), atelectasis (n = I),
and pleural effusion (n = 1). Descriptions
of the abnormalities
were not provided
for 8 cases.

Mortality
Hypersensitivity
reactions were possible causes of death in 19 cases, 8 of them

S. HETHERINGTON

ET AL.

Table II. Number and frequency of most common (210%) initial and rechallenge symptoms in 128 rechallenge cases of hypersensitivity to abacavir from 1996 through
2000.
Initial Presentation,
No. (%)

Symptom
Fever
Rash
Gastrointestinal symptoms+
Constitutional symptomsi
Respiratory symptoms
Chills
Abnormal hepatic function
Headache
Pruritus
Abnormal blood count
Hypotension
Abnormal renal function
Edema
Tachycardia

Rechallenge Presentation,
No. (%)

72 (56)
65 (5 1)
58 (45)
40 (31)
19 (15)
16 (13)
14(11)
13 (IO)

91
80
56
44
27
26
25

(71)
(63)
(44)
(34)
(21)
(20)
(20)

12 (9)
15 (12)
17 (13)
32 (2.5)
13 (10)
15 (12)
14(11)

12 (9)
11 (9)
7 (5)
6 (5)
6 (5)

1 (1)

P*

0.014
0.059
0.801
0.594
0.193
0.091
0.056
0.833
0.542
0.230
0.00 1
0.095
0.040
0.001

*Chi-square test.
Including
iIncluding
Including

diarrhea, nausea, vomiting, and abdominal pain.

lethargy, malaise, arthralgia, and myalgia.
tachypnea, respiratory distress, pharyngitis, pneumonia,

from the 30,595 participants in clinical trials and expanded-access programs, resulting in a case fatality rate of 0.03% (3 per
10,000 patients). Six of the 19 (3 1.6%)
deaths occurred after rechallenge
with
abacavir. The time from rechallenge to the
onset of symptoms was <l day in 5 patients and not specified in 1 patient. Three
of these cases came from clinical trials
and 3 from postmarketing reports. The remaining 13 deaths (5 cases from clinical
trials and 8 from postmarketing
reports)
occurred during the initial reaction (ie, no
rechallenge described). In these cases, the
time to onset of symptoms ranged from 9
to 90 days. In some cases, abacavir was
continued
because symptoms were ascribed to conditions other than hypersen-

and cough.

sitivity to abacavir; in other cases, the presence of comorbid conditions

(eg, lymphoma of the liver) was likely to have contributed to the risk of mortality.
Eleven of the 19 (57.9%) patients who
died had respiratory symptoms after initial
exposure to abacavir. Possible attribution
of hypersensitivity
symptoms to an acute
respiratory tract infection resulted in a delay in the withdrawal of abacavir in 4 cases
and may have led to the decision to rechallenge patients with abacavir in 2 cases.

DISCUSSION
Hypersensitivity
reactions are unexpected
adverse events that are considered
by
some to involve an immune response.61y

1609

CLINICAL THERAPEUTICS

Cases have been reported with a broad

range of medications, including antiretroviral agents. w~ In general, hypersensitivity reactions are more common and more
serious in the HIV-infected
population
than in other groups.y,2 This retrospective review of hypersensitivity
reactions
to abacavir is intended to provide the clinician with an understanding of the clinical profile of this idiosyncratic reaction.
Additional studies of the epidemiologic
risk factors, mechanisms,
and potential
pharmacogenetic
associations
of hypersensitivity reactions are in progress.
Idiosyncratic reactions, consisting primarily of cutaneous eruptions, have been
reported more frequently with the nonnucleoside reverse transcriptase inhibitors
(NNRTIs) nevirapine,
and efavirenz
than with NRTIs~~ and protease inhibitors.s Skin rashes after the administration of nevirapine have been reported
in 17% to 32% of patients, and systemic
symptoms (fever) may also be present.15.
Stevens-Johnson
syndrome has been reported in 0.37~ of nevirapine recipients.5,2
In a small study in 25 patients receiving
nevirapine and zidovudine,23 8 developed
fever and rash, 3 of whom continued to
receive treatment while having a mild
rash. Nevirapine has also been associated
with another idiopathic syndrome called
DRESS (drug rash with eosinophilia and
systemic symptoms). IJ
The hypersensitivity
reaction to abacavir described here differs in several important ways from the more common cutaneous reactions described with NNRTIs.
First, rash is not a consistent element of
the reaction, and the rash observed in these
cases did not progress to Stevens-Johnson
syndrome. The severe morbidity and mortality of abacavir hypersensitivity
reactions are due to systemic symptoms,

1610

specifically hypotension. It is possible to

continue treatment in the presence of a
mild rash caused by NNRTI therapy, but
the progressive severity of the systemic
symptoms of abacavir hypersensitivity
dictates immediate
discontinuation
of
therapy. Finally, reintroduction
of abacavir after the resolution of an initial hypersensitivity reaction, which resulted in
hypotension in 1 of 4 patients and 6 fatalities, should not be attempted. There
have been rare reports of a reaction to indinavir that is indistinguishable
from hypersensitivity
to abacavir, including the
rechallenge reaction.d-h Thus, although
severe cutaneous
reactions
have been
called hypersensitivity
reactions in the
literature, we prefer to reserve the term
hypersensitivity for those idiosyncratic reactions in which systemic symptoms predominate and are clinically more significant than rash, when present.
Features of the hypersensitivity
reaction to abacavir suggest an immunemediated mechanism but do not match
any of the Gel1 and Coombs classifications precisely. Although the rapid response to abacavir rechallenge is consistent with an immunoglobulin
E-mediated
reaction, bronchospasm,
angioedema, or
eosinophilia
was rarely observed in our
cases. Similarly, the clinical presentation
in hypersensitivity
reactions to abacavir,
even when hypotension was present, differed from classic anaphylaxis, which is
also presumed to be mediated by immunoglobulin
E.6 Studies are in progress
to quantify the presence of antiabacavir
antibodies
in patients with hypersensitivity to abacavir. It is possible that
hypersensitivity
to abacavir follows a
mechanism as described in the hapten hypothesis, 8.y.28by which a reactive intermediate in the metabolism
of abacavir

S. HETHERINGTON

ET AL.

would covalently bind to a protein, creating

an immunologically
reactive metaboliteprotein adduct. On interaction
of the
metabolite-protein
adduct with cells of
the immune system, the release of cytokines would result in development
of
symptoms. Studies are under way to characterize the immunologic processes associated with hypersensitivity
to abacavir.
Diagnosis of hypersensitivity
reactions
is based on the clinical history and physical examination. Skin testing was reportedly positive in 1 case of hypersensitivity
to abacavir.?O Low-level lymphoproliferative responses to abacavir in vitro were
observed in another patient. These cases,
however, are anecdotal, and the tests have
not been rigorously studied. With the exception of penicillin, skin testing for adverse reactions to medications,
particularly hypersensitivity
reactions, has not
proved sufficiently sensitive or specific to
guide subsequent patient management.2
In the absence of diagnostic tests, physicians should maintain a high level of
suspicion when evaluating patients presenting with symptoms suggesting a hypersensitivity reaction, particularly during
the initial 6 weeks of therapy with abacavir. Because adverse events are common
during the initial treatment phases of HIVI infection, the presence of any single
symptom, including rash, is not sufficient
to identify a hypersensitivity
reaction to
abacavir. Our guidance for clinical protocols using abacavir has been that in patients who develop skin rash alone without systemic symptoms, abacavir may be
continued, with the warning that it should
be discontinued and the patient evaluated
if other symptoms arise.
In the present analysis, the median time
to onset of symptoms of a hypersensitivity reaction was 11 days, similar to that

seen with other hypersensitivity

reactions. In 98 (6%) of the 1682 cases with
a known time to onset, the onset of symptoms began on the first day of treatment,
which has been described with hypersensitivity reactions to other medications.2h
The reason for this early onset is not
known. These may have represented cases
of sensitization by a previous medication.
although no cross-sensitivity between abacavir and other medications has been identified to date. The precise time to onset of
individual symptoms was not analyzed,
but investigators provided anecdotal descriptions of the evolution of symptoms:
fever and GI symptoms were often the
first signs, whereas the appearance of rash
lagged by a day or more. Additional studies are in progress to better define the time
course of individual symptoms associated
with hypersensitivity
to abacavir.
Most simply, hypersensitivity
to abacavir was managed by discontinuation
of
the drug. No data are available on the efficacy of corticosteroids
or antihistamines in preventing or treating hypersensitivity reactions to abacavir. Recent data
indicate that corticosteroids do not reduce
the frequency of cutaneous reactions to
NNRTIs,~,~ but these reactions are likely
to be mechanistically
different from hypersensitivity reactions to abacavir.
If hypersensitivity
to abacavir is an immune process, one might ask whether interruptions
in abacavir therapy lead to
priming or immune boosting. A recent report evaluating 161 patients receiving an
abacavir-lamivudine-zidovudine
regimen
for 24 weeks found no correlation
between interruption of abacavir therapy and
increased risk for hypersensitivity.
Although another recent report described a
patient with a rechallenge-like
reaction
after interruption and reinstitution of abac-

1611

CLINICAL THERAPEUTICS

avir, there is currently no evidence to

suggest that interrupting
and restarting
abacavir increases either the frequency or
severity of a subsequent hypersensitivity
reaction.
Although we have attempted to provide
a comprehensive review of hypersensitivity to abacavir, there are several limitations to our analysis. Some cases from the
expanded-access
program and postmarketing reports were poorly documented,
and full details were not always available.
The majority of hypersensitivity cases included in this review originated with the
large abacavir expanded-access
program,
which enrolled - 15,000 subjects worldwide. These were patients with advanced
disease who were receiving more medications and were subject to more complications of HIV-l infection than patients in
clinical trials. Because of the conservative
approach appropriate to the management
of patients with symptoms and signs consistent with this reaction, some cases identified by physicians may not have been
true cases of hypersensitivity
(ie, falsepositives) and the incidence of hypersensitivity may thus be overestimated. We do
not believe the incidence of hypersensitivity in clinical trials is underestimated,
because our review included all cases that
were clinically compatible with the clinical syndrome, irrespective of the diagnosis or causality ascribed by the reporting
investigator. No diagnosis of hypersensitivity was excluded, regardless of the
specifics of the data provided.

CONCLUSIONS
A hypersensitivity
reaction to abacavir
will appear as a treatment-limiting
event
in -5% of patients. Hypersensitivity should
be considered when a patient receiving

1612

abacavir develops evidence of a multisystem disorder. The development of hypersensitivity to abacavir requires permanent
discontinuation
of abacavir or abacavircontaining products.

ACKNOWLEDGMENTS
The authors
patients
trials

thank all the investigators

who participated

of abacavir.

acknowledge
editing

The authors

Belinda

and

in the clinical
gratefully

Ha for writing

and

assistance.

REFERENCES
Staszewski S, Keiser P, Montaner J, et
al. Abacavir-lamivudine-zidovudine
vs
indinavir-lamivudine-zidovudine
in antiretroviral-naive
HIV-infected
adults: A
randomized equivalence trial. JAMA. 200 I ;
285:1155-l 163.
Saez-Llorens X, Nelson RP Jr, Emmanuel
P, et al. A randomized, double-blind study
of triple nucleoside therapy of abacavir,
lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated
human immunodeficiency
virus type Iinfected children. Pediatrics [serial online].
2001; 107:E4. Available at: http://www.
pediatrics.org/cgi/content/fulVl07/l/e4.
Accessed August 6, 2001.
Saag MS, Sonnerborg A, Torres RA, et al,
for the Abacavir Phase 2 Clinical Team.
Antiretroviral effect and safety of abacavir
alone and in combination with zidovudine
in HIV-infected
adults. AIDS. 1998; 12:
F203-F209.
Staszewski S, Katlama C, Harrer T, et al.
A dose-ranging
study to evaluate the
safety and efficacy of abacavir alone or in
combination with zidovudine and lamivudine in antiretroviral treatment-naive subjects. AIDS. 1998; I2:Fl97-F202.

S. HETHERINGTON

ET AL.

5. Cutrell A, Edwards M, Steel H, et al. Risk

factor analysis for hypersensitivity
reactions to abacavir. Poster presented at: 1st
IAS International
Symposium
on HIV
Pathogenesis and Treatment; June 8-l I,
200 I ; Buenos Aires. Argentina. Poster 537.

14. Bourezane Y, Salard D, Hoen B, et al.

DRESS (drug rash with eosinophilia and
systemic symptoms) syndrome associated
with nevirapine therapy. Clin Infect Dis.
1998;27:1321-1322.

6. Shapiro LE, Shear NH. Mechanisms of

drug reactions: The metabolic track. Sem
Cutaneous Med Surg. 1996; 151217-227.

DE, Kim NY,

15. Warren KJ, Boxwell
Drolet BA. Nevirapine-associated
StevensJohnson syndrome. Lancet. 1998;35 1:567.
Letter.

7. deShazo RD, Kemp SF. Allergic reactions

to drugs and biologic agents. JAMA. 1997;
278:1895-1906.

16. Mills G, Morgan J, Hales G, Smith D.

Acute hypersensitivity
with delavirdine.
Antiviral Ther: 1999;4:5 1. Letter.

8. Park BK, Pirmohamed M, Kitteringham

NR. Role of drug disposition in drug hypersensitivity: A chemical, molecular, and
clinical perspective.
Chem Res Toxicol.
1998; 11:969-988.
9. Pohl LR, Satoh H, Christ DD, Kenna JG.
The immunologic and metabolic basis of
drug hypersensitivities.
Annu Rev Pharmacol Tbxicol. 1988;28:367-387.
IO. McNeely MC, Yarchoan R, Broder S,
Lawley TJ. Dermatologic complications
associated with administration
of 2,3dideoxycytidine
in patients with human
immunodeficiency
virus infection. J Am
Acad Dermatol. 1989;21:1213-1217.
Il. Carr A, Penny R, Cooper DA. Allergy and
desensitization
to zidovudine in patients
with acquired immunodeficiency
syndrome (AIDS). J Allergy Clin Immunol.
1993;91:683-685.
to
12. Wassef M, Keiser P. Hypersensitivity
zidovudine: Report of a case of anaphylaxis and review of the literature. Clin In,fectDis. 199.5;20:1387-1389.
13. Tancrede-Bohin E, Grange F, Boumerias
I, et al. Hypersensitivity syndrome associated with zalcitabine
therapy. Lancet.
1996;347:97 1. Letter.

17. Bossi P, Colin D, Bricaire F, Caumes E.

Hypersensitivity syndrome associated with
efavirenz therapy. Clin Infect Dis. 2000;30:
227-228.
18. Bonfanti P, Capetti A, Riva P, et al. Hypersensitivity reactions during antiretroviral regimens with protease inhibitors. AIDS.
1997;11:1301-1302.
19. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Erg1 / Med.
1994;331:1272-1285.
20. Koopmans PP, van der Ven AJ, Vree TB,
van der Meer JW. Pathogenesis of hypersensitivity reactions to drugs in patients
with HIV infection: Allergic or toxic?
AIDS. 1995;9:217-222.
21. Miller V, Staszewski S, Boucher CAB,
Phair JP. Clinical experience with nonnucleoside reverse transcriptase inhibitors.
AIDS. 1997;l l(Suppl A):S157-S164.
22. Barner A, Myers M. Nevirapine
and
rashes. Lancer. 1998;35 1: 1133. Letter.
23. Carr A, Vella S, de Jong MD, et al, for
the Dutch-Italian-Australian
Nevirapine
Study Group. A controlled trial of nevirapine plus zidovudine versus zidovudine
alone in p24 antigenaemic HIV-infected
patients. AIDS. 1996;10:635-641.

1613

CLINICAL THERAPEUTICS

24.

2s.

26.

27.

Rietsema WJ. Fever, erythroderma,

abdominal pain, and renal failure following
initiation of indinavir therapy. C/in Irz&~r
Dis. 1997:25: 126% I 269.
Rijnders B, Kooman J. Severe allergic reaction after repeated exposure to indinavir. Clin Infect Dis. 1998;26:523-524.
Dieleman JP, int Veld B. Borleffs JCC,
Schreij G. Acute respiratory failure associated with the human immunodeficiency
virus (HIV) protease inhibitor indinavir in
an HIV-infected patient. Clin Infect Dis.
1998;26:1012-1013,
Joint Task Force on Practice Parameters,
the American Academy of Allergy, Asthma
and Immunology, and the Joint Council of
Allergy, Asthma and Immunology. Executive summary of disease management of
drug hypersensitivity: A practice parameter. Ann Allergy Astkmn Immunol.
1999;
83:665-700.

28.

Uetrecht JP. New concepts in immunology relevant to idiosyncratic drug reactions: The danger hypothesis and innate
immune system. Chern Res Tosicol. 1999;
12:387-395.

29.

Vyakarnam A, King D, Boaz M, et al.

Abacavir induced hypersensitivity in HIV
infected individuals is associated with an
increased frequency of ThO T cells. AIDS.
2000;14:S65.

30.

Kinaciyan T, Kuhn M, Schneeberger A,

Sting1 G. Hypersensitivity
syndrome to
abacavir-confirmation
by skin testing.
Allergy.

2000;55:

153.

31. Escaut L. Liotier JY, Albengres E, et al.

Abacavir rechallenge has to be avoided in

Address

correspondence

GlaxoSmithKline,
corn

1614

Research

case of hypersensitivity
1999;13:1419-1420.

AIDS.

32. Adkinson NF Jr. Risk factors for drug allergy. J Allergy Clin Immunol.
1984;74:
567-572.

33. Knowles SR, Uetrecht J, Shear NH. Idiosyncratic drug reactions: The reactive
metabolite syndromes. Lance?. 2000;356:
1587-1591.
34. Knobel H, Miro JM, De-Miguel V, et al.
Efficacy of a short-term prednisone regimen in nevirapine-associated
rash prevention: A double-blind
placebo-controlled
clinical trial. Results of the GESIDA 09/99
study. Presented at: 40th Interscience Conference on Antimicrobial
Agents and
Chemotherapy:
September 17-20. 2000;
Toronto, Canada. Abstract L- 15.
35. Robinson P. Examination of trials to prevent nevirapine (NVP)-associated
rash.
Presented at: 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy; September 17-20. 2000; Toronto,
Canada. Abstract 1554.
36. Thompson M, Shaefer MS, Williams V. et
al. Interruptions in abacavir dosing are not
associated with increased risk of hypersensitivity in the HEART (NZTA4006)
study. Presented at: 40th Interscience Conference on Antimicrobial
Agents and
Chemotherapy;
September 17-20. 2000;
Toronto, Canada. Abstract L- 14.
37. Frissen PHJ, de Vries J, Weigel HM,
Brinkman K. Severe anaphylactic shock
after rechallenge with abacavir without
preceding hypersensitivity.
AIDS.
2001;
lS:289. Letter.

to: Seth Hetherington,

Triangle

reaction.

MD, HIV/O1 Clinical Development.

Park, NC 27709. E-mail: svh3 1379@glaxowellcome.