1. Asian Biomedicine Vol. 4 No. 4 August 2010; 505-513
Practice Guidelines
Thai national guidelines for the use of antiretroviral
therapy in pediatric HIV infection in 2010
Thanyawee Puthanakita, Auchara Tangsathapornpongb, Jintanat Ananworanichc, Jurai Wongsawatd, Piyarat
Suntrattiwonge, Orasri Wittawatmongkolf, Jutarat Mekmullicag, Woraman Waidabh, Sorakij Bhakeecheepi,
Kulkanya Chokephaibulkitf, for the Thai National HIV Guidelines Working Group
a
Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330;
b
Department of Pediatrics, Faculty of Medicine, Thammasat University Hospital, Pathumthani 12120;
c
The Thai Red Cross AIDS Research Center, Bangkok 10330; dBamrasnaradura Institute, Ministry of
Public Health, Bangkok; eQueen Sirikit National Institute of Child Health, Bangkok 10400; fDepartment
of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700; gDepartment
of Pediatrics, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Bangkok 10220; hCharoenkrung
Pracharak Hospital, Bangkok 10120; iNational Health Security Office, Bangkok 10120, Thailand
With better knowledge and availability of antiretroviral treatments, the Thai National HIV Guidelines Working
Group has issued treatment guidelines for children in Thailand in March 2010. The most important aspects of
these new guidelines are detailed below.
ART should be initiated in infants less than 12 months of age at any CD4 level regardless of symptoms and
in all children at CDC clinical stage B and C or WHO clinical stages 3 and 4. For children with no or mild symptoms
consider CD4-guided thresholds of CD4 <25% (children aged one to five years) or CD4 <350 cells/mm3 (children
5 years or older). The preferred first-line regimen in children aged < 3 years is AZT+3TC+NVP. For children >3
years of age the preferred regimen is AZT+3TC+EFV. If an infant has previously been exposed to NVP perinatally,
use AZT+3TC+LPV/r as empirical first regimen. In adolescents, consider TDF+3TC+EFV.
The preferred ARV treatment in children who failed first line regimens of 2NRTI+NNRTI (Salvage treatment)
comprises 2NRTI (guided by genotype) +LPV/r, and an alternative regimen is 2NRTI (guided by genotype) +ATV/
r (use in cases with dyslipidemia who are six years or older). In cases with extensive NRTI resistance with no
effective NRTI option available, double boosted PI with LPV/r+SQV or LPV/r+IDV can be considered. Consultation
with an expert is recommended.
Laboratory monitoring is recommended for CD4 and every six months. Viral load at least at 6 and 12 months
after initiation or change of regimen, then yearly thereafter. More frequent viral load monitoring is advised for
cases with unsuccessful virologic response, infants, children with imperfect adherence, or those using of third
line regimens. Toxicity monitoring depends on the drug received, at least every six months, and more often as
clinically indicated. These include, but are not limited to, complete blood count, renal function tests, liver function
tests, urinanalysis, and lipid profiles. Therapeutic drug monitoring is recommended in cases that have ARV-related
toxicity, receiving non-standard dosing or regimens, using double boosted PI, and in those with renal or hepatic
impairment.
Keywords: HIV, pediatrics, Thai guidelines
The systematic treatment program for human
immune deficiency virus (HIV)/acquired immune
deficiency syndrome (AIDS) is continuously evolving
in the Thai medical community. The Ministry of Public
Health, and later on, the National Health Security
Organization (NHSO) has been providing free access
Correspondence to: Kulkanya Chokephaibulkit, MD. Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University,
2 Prannok Road, Bangkok-noi, Bangkok 10700, Thailand. E-mail: sikch@mahidol.ac.th
2. 506
T. Puthanakit, et al.
to antiretroviral therapy (ART) and monitoring for
more than 10 years. The National Guidelines have
been updated as knowledge and availability of
treatment and care have improved. The Thai National
HIV Guidelines Working Group is composed of
pediatricians, academicians, researchers, and
nongovernment organizations (NGOs) with expertise
in HIV and AIDS, and is supported by the Bureau of
AIDS, TB, and STD, and Ministry of Public Health
(MOPH). Representatives from the NHSO and the
MOPH have joined the Working Group. The guidelines
were issued in March 2010.
The treatment guidelines presented here aim
to provide a summary of recommendations for
treating HIV-infected children and adolescents in
Thailand. The Working Group reviewed and made
recommendations based upon data from Thai children
and from recently published WHO [1], PENTA [2]
and US guidelines [3].
Current situation of Pediatric HIV/AIDS in
Thailand
The major route of HIV infection in Thai children
is mother to child transmission. The cumulative
numbers of perinatally HIV-infected Thai children are
estimated to be 15,000 to 20,000, of which more than
8,000 children have received antiretroviral therapy
through the National program. HIV prevalence among
pregnant women at antenatal care clinics has been
reduced from about 2% in 1999 to 0.74% in 2009.
There are about 6,000 infants born to HIV-positive
mothers each year, leading to 200-400 newly HIVinfected infants annually.
Diagnosis of HIV in children younger than 18
months of age
HIV infection should be diagnosed early in life to
provide appropriate treatment and care. The diagnosis
can be made by positive HIV RNA or DNA
polymerase chain reaction (PCR) as early as one
month of age.
HIV infection can be excluded if a child had either
1) two negative HIV PCR tests, of which the first
test is performed at > one month of age and the
second test is performed at > four months of age; 2)
two negative HIV antibody test after six months of
age; or 3) one negative PCR at > four months of age
and one negative HIV antibody test after six months
of age plus no clinical signs or symptoms compatible
with HIV infection [4].
In the clinical care for infants born from HIVpositive mother in Thailand, it is recommended to have
at least one HIV antibody test preferable at 18 months
to definitely exclude HIV infection. At 12 months, the
majority of infants who are not infected have negative
HIV antibody tests. However, 5-10% of HIV
uninfected infants may have persistent maternal
antibodies. The infants with positive HIV antibody tests
at 12 months should have the test repeated at 18
months. It is noted that combination serologic tests
(antigen-antibody combined tests) may be able to
detect very low levels of HIV antibodies and report
positive results in some HIV-uninfected children at 18
months of age. Therefore, it is recommended not to
use the combination test for diagnosis of perinatal
infection.
Baseline evaluations before the initiation of ART
A detailed history of any possible previous
exposure to ART in a child should be documented.
Children should be examined and evaluated for
opportunistic infections (OI), especially tuberculosis.
Cotrimoxazole (TMP/SMX), is recommended in all
HIV-exposed infants until HIV infection is excluded
and in all HIV-infected infants regardless of CD4
levels. TMP/SMX is also recommended in HIVinfected children younger than five years of age who
have CD4 percentage lower than 15%, and in older
than five years who have CD4 count less than 200
cells/mm3. The common side effects of TMP/SMX
are rash or cytopenia, which might be confused with
ART toxicity if started at the same time. Baseline preART evaluations should include CD4 cell count and
percentage, hematology, biochemistry, (e.g. AST, ALT),
and profile testing for other blood-borne infections,
especially hepatitis B. Moreover, the evaluation of
psychosocial aspects including whether the child has
been informed about their HIV status and their
readiness to take antiretroviral therapy are crucial.
Clinical monitoring and measurements of CD4 level
should be repeated every six months in well children
who do not need to start ART, and more frequently in
infants and in older children approaching treatment
thresholds.
When to start antiretroviral therapy (ART)
Because disease progression among HIV-infected
infants is unpredictable and has high morbidity and
mortality, ART should be started urgently in all infants,
as soon as the diagnosis of infection is confirmed
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Thai national pediatrics HIV guidelines
irrespective of the clinical or immunological stage [5].
ART should be initiated in all children with symptomatic
diseases (CDC clinical stage B or C or WHO stage 3
or 4) who are > one year of age. For children who
have minor symptoms, ART initiation should be based
on age-specific CD4 thresholds (Table 1). Baseline
viral load is not recommended as criteria to initiate
ART. Importantly, issues likely to affect adherence
should always be considered and addressed before
starting therapy.
What antiretroviral regimens to start with
The current preferred first-line ART regimen for
previously untreated children comprises two
nucleoside reverse transcriptase inhibitors (NRTIs)
with a non-nucleoside reverse transcriptase inhibitor
(NNRTI).
The preferred NRTI combination is zidovudine
(ZDV) and lamivudine (3TC) and the alternative
combination is stavudine (d4T) and lamivudine
(3TC). AZT is preferred because it has less longterm toxicities, such as lipodystrophy, compared to
stavudine. However, children with low baseline
hemoglobin <8 g/dL should start with d4T and switch
to AZT after 6-12 months of treatment. In adolescents
who weigh > 40 kg or with Tanner stage IV, tenofovir
(TDF) and 3TC is a preferred because the dosing is
once daily, which may improve adherence (Table 2).
507
The preferred NNRTI is nevirapine (NVP) for
children age < 3 years, and efavirenz (EFV) for older
children. NVP has benefits over EFV in terms of
formulations available, i.e. syrup, tablet, and fixed dose
combination GPOvir (d4T/3TC/NVP) or GPOvir-Z
(AZT/3TC/NVP). However, NVP has more side
effects such as rash and hepatotoxicity [6]. Some
reports showed better virological efficacy of EFV over
NVP [7].
Infants who are exposed to NVP as part of
prevention of mother to child transmission have
20-57% risk of harboring NVP resistance [8, 9].
Therefore, the first line regimen should be two NRTIs
and boosted lopinavir (LPV/r), the only protease
inhibitor (PI) available for infants [10]. Genotypic
testing for drug resistance prior to initiating ARV is
recommended. After the first six months of treatment
with a PI-based regimen, if the patient has viral
suppression and the genotypic testing of the sample
prior to ARV initiation has no evidence of NVP
resistance, the regimen can be switched to NNRTIbased regimen.
For children who had recent opportunistic
infections, there are some special considerations such
as timing of the start of antiretroviral drugs, drug
interactions, and the risk of developing immune
reconstitution inflammatory syndrome (IRIS). In
general, antiretroviral therapy should be initiated within
Table 1. Criteria for initiation of antiretroviral therapy among HIV-infected children.
Age <1 year
Age 1-5 years
Age > 5 years
Clinical staging criteria
All
Immunological criteria
%CD4 or CD4 cell count
All
CDC category B, C
or WHO stage 3, 4
%CD4 <25
CDC category B, C
or WHO stage 3, 4
CD4 <350 cells/mm3
Table 2. The recommended first line regimen in Thai children.
Age <3 years
Age >3 years
Preferred regimens
Preferred regimens for
adolescents (weight >40 kg
or Tanner stage IV)
AZT+3TC+NVP
AZT+3TC+EFV
-
TDF+3TC+EFV
Alternative regimens
d4T+3TC+NVP
AZT+3TC+NVP
d4T+3TC+EFV
d4T+3TC+NVP
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T. Puthanakit, et al.
two to eight weeks after starting treatment for OI.
Among children who have a low baseline CD4 level,
the risk of developing IRIS is about 20% [11].
However, this should not be a reason to delay initiation
of antiretroviral treatment when indicated. The most
problematic drug interactions with ART are with
rifampicin in children with tuberculosis (TB) coinfections. Rifampicin reduces EFV levels by 25%,
however data from Thai HIV-infected adult patients
showed that the standard dose of EFV provide
adequate plasma levels [12]. Recent data also showed
that despite drug interactions between rifampicin and
NVP, the standard dose of NVP could be used [13].
However, rifampicin significantly reduces PI levels
and these drugs must not be used together. In case
patients need PI, the treatment option depends on
immune status. If a patient has a low CD4 level
and needs a PI-containing salvage regimen, the
antiretroviral drug has a higher priority. Therefore,
one should avoid rifampicin and modify antituberculous drugs using quinolones or
aminoglycosides. If a patient has a high CD4 level,
PI-based antiretroviral treament initiation should be
postponed until the completion of a two-month
intensive anti-tuberculous treatment with rifampicin.
The maintenance phase without rifampicin should be
used with PI containing regimens.
Monitoring while on ART
The first six months after initiation of treatment
is a vulnerable period due to potential drug toxicity,
IRIS, or poor adherence. It is crucial to monitor for
clinical response, which would include confirming
general well being, changes in body weight, and
problems related to ART or IRIS. Follow-up visits
should be scheduled every month until stable, then
extended to every two to three months. It is important
to specifically check for adherence to therapy at every
clinic visit.
The CD4 cell count should be monitored every
six months. Plasma HIV viral load should be monitored
at least at 6 months and 12 months after treatment
initiation and yearly thereafter. In cases where the
virologic response is not as successful as expected,
more frequent virologic monitoring is required. More
frequent clinical and laboratory monitoring are
required in infants, as well as in cases of imperfect
adherence, especially at the start or change of therapy.
Serum testing for drug toxicity should be done
routinely every six months. It should include complete
blood count, liver function tests, renal function tests,
and lipid profile. Some antiretroviral drugs have specific
drug toxicities which require monitoring, such as NVP
(alanine aminotransferase, ALT, at two to four weeks
after initiation), AZT (complete blood count after three
months after initiation), indinavir (IDV), and TDF
(urinalysis and creatinine every three months).
Diagnosis of treatment failure
Treatment failure can be detected through
virologic, immunologic, or clinical criteria [3]. Virologic
failure is usually detected earlier than immunologic
failure. However, the lapsed time differs in each
individual ranging from few months to few years.
Clinical failure usually occurs after a period of
immunologic failure. Immunologic failure or clinical
failure must concur with virologic failure in order to
indicate treatment failure.
1) Clinical failure is defined as one of the following:
• Abnormal or regression of developmental
milestones.
• Poor growth without other causes.
• Appearance of new, or progression of, HIVrelated conditions or opportunistic infections. Due to
the high prevalence of tuberculosis in Thailand,
tuberculosis of the lung or lymph node does not
necessarily indicate clinical failure, especially if there
is an otherwise good response to treatment.
2) Immunologic failure is determined based on at least
two measurements of CD4, at least one week apart.
Some acute conditions or infections may cause a
transient drop in CD4. Immunologic failure is defined
as one of the following:
• Inadequate immunologic response to treatment:
- For children younger than five years with
baseline CD4<15%, an increase of CD4 percentage
of less than five after one year of treatment
- For children five years or older with baseline
CD4 <200 cells/mm3, an increase of CD4 of less than
50 cells/mm3 after one year of treatment.
• Decrease of CD4 levels:
- For those with baseline CD4 percentage <15%,
a sustained decrease of at least 5% after treatment
initiation, i.e., decrease from 15% to 10%.
- Any decrease in CD4 percentage or count of
more than 30% over a six-month period.
3) Virologic failure is defined as one of the following:
Inadequate virologic response to treatment
• In infants younger than 12 months of age, the HIV
RNA level (viral load) is >50 copies/mL after one year
of treatment.
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Thai national pediatrics HIV guidelines
• In children older than one year of age, the viral
load is >50 copies/mL after six months of treatment
• Increase of viral load to >1,000 copies/mL in those
who previously had good viral suppression. The viral
load of 50-1,000 copies/mL may be a transient viral
blip from imperfect adherence or other temporary
effects. In such cases, the viral load measurement
should be repeated at one to three months after
adherence counseling.
Antiretroviral treatment in children with
treatment failure
Most treatment failures are caused by poor
adherence. Therefore, adherence must be evaluated
and counseling must be provided to patients and their
families. Treatment failure may be from inappropriate
treatment regimens, e.g., dual NRTI that was
commonly used when antiretroviral drugs were not
widely available. Some children may acquire resistant
virus from the beginning, such as infants exposed to
perinatal single dose NVP. These children are at risk
for treatment failure with NNRTI regimens. A baseline
genotypic assay is a useful guide to treatment in such
cases.
The new treatment regimen should be guided
by genotypic assay results. In Thailand, it is
recommended to perform a genotypic assay when the
viral load is >2,000 copies/mL and the child has been
receiving treatment or discontinued treatment no
longer than one month.
It is important that the new treatment or salvage
regimen be started soon after virologic failure to
prevent accumulation of resistance mutations.
Prolonged use of failing regimens causes selective
pressures that result in more resistance mutations and
may jeopardize future options. For example, prolonged
use of NRTI in patients with thymidine analogue
mutations (TAMs) will cause accumulation of more
TAMs; and prolonged use of NNRTI in patients who
have NNRTI resistance mutations may cause further
resistance to etravirine, (a new NNRTI drug) [14].
However, the new treatment regimen should not be
started until good adherence is ensured.
Choosing the new regimen in children who fail
2NRTI+1NNRTI regimens (Fig. 1)
• Preferred regimen: 2NRTI plus LPV/r[15]
(selection of NRTI guided by genotype)
• Alternative regimens: 2NRTI plus boosted
atazanavir (ATV/r). Selection of NRTI is guided by
509
genotype (see below). ATV is approved in children
six years or older. This regimen is most appropriate in
those with dyslipidemia [16].
Double boosted PI with boosted lopinavir and
saquinavir (LPV/r+SQV) [17] or boosted lopinavir and
indinavir (LPV/r+IDV) [18], with or without NRTI.
These regimens are considered only in children who
have no effective NRTI available, i.e., with extensive
NRTI resistance mutations and cannot use TDF or
ABC. Initiating these regimens requires expert
consultation. Children receiving double boosted PI
must be closely monitored for toxicities, especially
metabolic and renal. Children who receive these
regimens and had complete viral suppression for more
than one year should be considered to switch to a
regimen comprising a single boosted PI plus NRTI(s).
Selection of NRTI for the new regimen guided
by genotypic assay
The genotypic resistance testing reports include
the gene mutations and the interpretation of ARV drug
susceptibility. The principles of interpreting genotypic
assay in order to select NRTI in the new regimen are
as follows [19]:
• Resistance mutations in reverse transcriptase (RT)
genes that confer resistance to most NRTIs, except
3TC and FTC, are called TAMs. When number of
TAMs is >4, most of the NRTIs will not be effective
except that TDF, ABC, and ddI may still be useful if
without K65R.
• The other multi-NRTI mutations are T69i and
Q151M. They confer resistance to all NRTIs. The
exception is that virus with Q151M are still susceptible
to TDF.
• The K65R mutation confers resistance to TDF,
ABC, and ddI, but is susceptible to AZT.
• The L74V and K65R mutations confer resistance
to ddI and ABC.
• The M184V mutation confers resistance to 3TC
and FTC. However, the virus with M184V is a less fit
virus, and therefore keeping the patient on 3TC or
FTC to sustain this mutation may have clinical benefits.
The M184 mutation also causes hyper-susceptibility
to AZT or TDF.
The guide to selecting NRTIs in the new regimen
in combination with LPV/r or ATV/r is as follows
(Fig. 1):
a) When there are < 4 TAMs and without Q151M
or T69i.
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T. Puthanakit, et al.
Fig. 1 Formulating a new or salvage regimen in children failing 2NRTI+NNRTI regimens.
The 2NRTI selected for new regimens after
failing AZT/d4T+3TC may be ddI+3TC, ddI+AZT,
ABC+3TC or ABC+ddI.
b) When there are >4 TAMs or with Q151M or
T69i, but without K65R.
The new regimen may be TDF+3TC or
TDF+ABC or TDF+AZT. Some experts recommend
TDF+AZT+3TC because AZT may prevent
development of K65R, and 3TC may decrease viral
fitness. TDF should only be used for salvage treatment
in children >30 kg or with Tanner stage IV. TDF should
not be used with ddI.
c) When there are >4 TAMs and with K65R but
unable to use TDF (e.g. too young)
There will be no effective NRTI available. In this case,
the regimens with double boosted PI should be
considered. 3TC may be added to reduce viral fitness.
However, some experts may consider the 2NRTIs as
in a) plus single boosted PI (LPV/r, ATV/r) with closely
viral load monitoring.
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Thai national pediatrics HIV guidelines
Salvage regimens in children who are infected
with three classes of resistance mutations [20]
Children experiencing extensive antiretroviral
therapy and have resistance mutations to NRTIs,
NNRTIs, and PIs, have been identified more often in
older children. The principle in designing the salvage
regimen is to use at least two active drugs plus recycle
NRTIs because NRTIs may still be useful even with
resistance mutations. The aim is to achieve complete
viral suppression. New drugs, such as darunavir,
maraviroc, etravirine, or raltegravir, may be needed
in compassionate programs or study trials. Expert
consultation is recommended.
In case new effective regimens are not available
in the near future, and the patient has a high CD4
level (e.g. over than 200 cells/mm3), 3TC monotherapy
may be considered to slow the disease progression,
yet not select further resistance mutations that may
jeopardize future options. The salvage regimen should
be initiated as soon as possible.
Salvage regimens in children who fail dual NRTI
regimens
Dual NRTI regimens (AZT or d4T + 3TC or ddI)
were often used in the past when ART availability
was limited. Children receiving dual NRTI regimens
will have virologic failures at some points. However,
there are many children who have been receiving dual
NRTIs with stable CD4 and clinical status. These
children should be tested for viral load and viral
resistance. Whenever possible, the treatment regimen
should be switched to highly active antiretroviral
therapy (HAART) to prevent emerging of resistance
even though their viral load is suppressed. For children
who had incomplete viral suppression, the genotypic
assay should be used to guide the design of the new
regimen. The following points are guides to formulate
the new regimen
- If the RT mutations are not extensive, TAMs <4
(please see above for NRTI selection), the preferred
new regimen is 2NRTIs+LPV/r.
- If there are >4 TAMs especially with K65R or unable
to use TDF, the preferred regimen is NNRTI (prefer
EFV) +LPV/r with or without NRTI.
Monitoring in children receiving salvage
regimens
Monitoring for efficacy and safety of treatment
During the early phases of the new treatment
regimen, patients should be closely monitored for
adherence and potential side effects. The CD4 and
511
viral load should be monitored at least at six months
and 12 months after switching to the new regimens.
The salvage regimens containing PI that may cause
metabolic side effects should be monitored for fasting
glucose and lipid levels. Children who receive TDF
and IDV should be monitored for renal function
(electrolytes, BUN, creatinine, and urinalysis). The
tests for safety monitoring should be performed every
three to six months or as clinically indicated.
Therapeutic drug monitoring (TDM)
Therapeutic drug monitoring is useful for patients
who receive IDV, double boosted PI regimens, or drugs
that may have interact with each other. Moreover,
patients using drugs at dosages different from what is
recommended, and patients with underlying kidney or
liver diseases should receive TDM. The drug level
monitored is the trough level after at least two weeks
of treatment. However, TDM in the patients receiving
IDV should also include the peak level at two to four
hours after drug administration, which correlates with
kidney toxicity. Expert consultation is required for drug
or dose adjustments.
Acknowledgement
The Thai National HIV Guidelines Working Group
thankfully acknowledges the participation of the
following colleagues in preparing these guidelines:
The Pediatric Committee of The Thai National
HIV Guidelines Working Group:
Auchara Tangsathapornpong, Benjawan Raluek,
Boonyarat Warachit, Boripat Donmon, Chitsanu
Pancharon, Chuenkamol Sethaputra, Jintanat
Ananworanich, Jurai Wongsawat, Jutarat Mekmullica,
Kulkanya Chokephaibulkit, Orasri Wittawatmongkol,
Peeramon Ningsanond, Peninnah Oberdorfer, Piyarat
Suntrattiwong, Pope Kosalaraksa, Pramot Srisamang,
Rangsima Lolekha, Rawiwan Hansudewechakul,
Rudiwilai Samakoses, Siriporn Pongjitsiri, Sirirat
Kasisedapan, Sorakij Bhakeecheep, Supichaya
Netsawang, Thanyawee Puthanakit, Veerachai
Watanaveeradej, Virat Sirisanthana, Wasana
Prasitsuebsai, Wittaya Petdachai, Woraman Waidab.
The Steering Committee of The Thai National HIV
Guidelines Working Group:
Achara Teeraratkul, Aree Kumpitak, Kulkanya
Chokephaibulkit, Manoon Leechawengwong, Michalle
McConnell, Peeramon Ningsanond, Praphan
Phanuphak, Sanchai Chasombat, Somnuek
Sungkanuparph, Taweesap Siraprapasiri, Wasun
Chantratita, Wichai Techasathit.
8. T. Puthanakit, et al.
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