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Indian Pediatr 2018;55:140-141 |
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HLA- B*5701 Allele in
HIV-infected Indian Children and its Association with Abacavir
Hypersensitivity
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Mamta V Manglani, Yashwant R Gabhale, Mamatha M Lala,
Rohini Sekhar and Dipti More
From Pediatric Centre of Excellence for HIV Care (PCoE),
Department of Pediatrics, Lokmanya Tilak Municipal Medical College and
General Hospital, Sion, Mumbai, India.
Correspondence to: Dr. Yashwant R. Gabhale, Deputy
Program Director, Pediatric Centre of Excellence for HIV Care (PCoE),
Lokmanya Tilak Municipal Medical College and General Hospital, Sion,
Mumbai-22, India.
Email: [email protected]
Received: August 08, 2016;
Initial review: November 30, 2016;
Accepted: November 06, 2017.
Published online: December 14, 2017.
PII:S097475591600099
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Objective: To determine the prevalence of
HLA-B*5701 allele in HIV-infected children, and to find its
association with Abacavir hypersensitivity. Methods:
Children (2 to 18 y) already on, or to be initiated on Abacavir were
included for PCR sequencing to detect HLA-B*5701. Outcome measures were:
proportion with HLA B*5701 allele and hypersensitivity with Abacavir.
Abacavir was stopped if patient tested positive for HLA-B*5701 allele.
Results: 100 children (median age 11 y) were enrolled; 10
were already on Abacavir. HLA-B*5701 positivity was observed in 11 (11%)
children. Two of these 11 children developed hypersensitivity after
initiation of Abacavir. Abacavir was thereafter stopped in all who
tested HLA-B*5701 positive, irrespective of the development of
hypersensitivity reaction. Conclusion: HLA-B*5701 allele was
present in 11 (11%) of HIV-infected children, of which two
developed Abacavir hypersensitivity. None of the patients without the
allele developed hypersensitivity.
Keywords: Antiretroviral drugs, Adverse effects,
Genetics, HIV, Treatment.
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A
bacavir (ABC) is a potent nucleoside reverse
transcriptase inhibitor, and is an integral part of antiretroviral
therapy (ART). It has good efficacy, fewer drug interactions and a
favorable long term toxicity profile. However, hypersensitivity is a
recognized treatment-limiting toxicity with its prevalence of
approximately 3.7% [1]. A significant association between ABC
hypersensitivity and the presence of HLA-B*5701 allele has been
established [2,3]. It is thought that a derivative of the Abacavir
prodrug binds to an antigen-presenting cleft unique to HLA-B*5701, which
explains why the drug does not cause a similar hypersensitivity syndrome
in carriers of other HLA-B alleles [4,5]. The prevalence of HLA-B*5701
allele varies in different races, ranging from 2% to 20% [6,7]. Abacavir
hypersensitivity and its association with the HLA-B*5701 allele has
hardly been studied in the Indian population. The present study was
conducted with the objective of determining the prevalence of HLA B*5701
allele in HIV-infected children, and to find out any association with
Abacavir hypersensitivity.
Methods
This prospective study was conducted from June 2013
to May 2014 at the Pediatric Centre of Excellence (PCoE) for HIV Care,
Lokmanya Tilak Municipal Medical College and General Hospital, Sion,
Mumbai. Institutional Ethics Committee approval was obtained. The
inclusion criteria were HIV-infected children between 2 years to 18
years of age, already on Abacavir-based regimen or soon to be initiated
on an Abacavir-based regimen. Children with a past history of skin
allergy were excluded. A written informed consent of parents for
children up to 12 years of age, and consent of parents as well as an
assent for adolescents (>12 years) was obtained. History and examination
findings were documented in a pre-designed case-record form. All
children were subjected to HLA-B*5701-associated HCP5rs2395029
genotyping by PCR sequencing at a NABL accredited laboratory (Metropolis
Labs) [8,9]. Patients were evaluated on a weekly basis for
hypersensitivity reactions (fever, rash, nausea and vomiting). Reports
were obtained within 1 to 2 weeks of collection of the sample. Abacavir
was stopped in all cases of HLA-B*5701 allele positivity. The
proportions were compared using chi square test or Fisher’s exact test
for expected cell counts. We used t-test for parametric data and
Mann-Whitney test for non-parametric data.
Results
A total of 100 children were enrolled during the
study period. The median age was 11 years (range 2 to 18 y; 61 males).
HLA-B*5701 was positive in 11/100 patients (11%). Abacavir was stopped
in these children as soon as reports were available. Of these 11
children, 9 had received ABC for less than 6 weeks, and two for more
than 6 weeks. Two of these 11 children developed hypersensitivity (one
on 7 th day and one on day 45
of ABC). The symptoms of reactions were fever and gastrointestinal
intolerance in both, and respiratory distress in one child. Symptoms
resolved in both these children after discontinuation of Abacavir.
Abacavir was taken for a median (range) duration of 7 (3 - 15) days in
those who were to be initiated on ABC and 88 (16 - 774) days in those
who were already on ABC. Age (P=0.25), gender (P=0.52),
baseline CD4 (P=0.29) and CD4 at enrolment (P=0.912) did
not impact the presence of the allele, or hypersensitivity to ABC (P=0.88,
1.0, 0.48 and 0.81 for age, gender, baseline CD4 and CD4 at enrolment,
respectively).
Discussion
The present study demonstrated 11% prevalence of HLA
B*5701 positivity among HIV-infected children at our center.
Hypersensitivity to Abacavir, irrespective of the HLA-B*5701 allele, was
found to be 2%. Those two out of eleven children positive for the allele
had a hypersensitivity, whereas none of the children negative for the
allele showed hypersensitivity reactions.
The presence of HLA-B*5701 allele and its impact on
hypersensitivity to Abacavir has been well established in studies
reported in literature [2,3,10-12]. However, a wide variation has been
found in different ethnic groups with prevalence of the allele ranging
from 2% to 3% in African-Americans to 20% in Asian population, with 5 to
8% in Caucasians, 4% among Thais and 3.4% in Cambodia [6,7]. Prevalence
in our population is much higher than that of the African-Americans and
Caucasians, and is more closer to data from the Asian population [6].
The limitation of our study was a small sample size
and a short follow-up period of treatment with ABC (for less than 6
weeks) in 9 of the 11 children, who were positive for the allele, making
it difficult to arrive at a true prevalence of hypersensitivity.
We conclude that HLA-B*5701 allele may be present in
about one out of every ten Indian children and is associated with higher
frequency of hypersensitivity. Larger studies from different settings
with a longer duration of follow-up are required before recommendations
about its routine screening are made.
Contributors: MM: conceptualized the study
and critically revised the manuscript for intellectual content; YG, MML:
supervised the management of patients, edited the manuscript, helped in
clinical care of the patients, and performed the data analysis; DM, RS:
managed the patient enrollment and follow-up, and also helped in writing
the manuscript. All authors approved the final version.
Funding: National AIDS Control
Organization (NACO), Ministry of Health and Family Welfare, Government
of India.
Competing interests: None stated.
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What This Study Adds?
•
Most deaths due to HFMD occur in children <3 yr of age, and
usually due to neurological and cardiac complications.
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