Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 Update

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 02/2012; 91(4):734-8. DOI: 10.1038/clpt.2011.355
Source: PubMed


Human leukocyte antigen B (HLA-B) is responsible for presenting peptides to immune cells and plays a critical role in normal immune recognition of pathogens. A variant allele, HLA-B*57:01, is associated with increased risk of a hypersensitivity reaction to the anti-HIV drug abacavir. In the absence of genetic prescreening, hypersensitivity affects ~6% of patients and can be life-threatening with repeated dosing. We provide recommendations (updated periodically at for the use of abacavir based on HLA-B genotype.


Available from: Munir Pirmohamed
734 VOLUME 91 NUMBER 4 | APRIL 2012 |
nature publishing group
Human leukocyte antigen B (HLA-B) is responsible for
presenting peptides to immune cells and plays a critical role in
normal immune recognition of pathogens. A variant allele, HLA-
B*57:01, is associated with increased risk of a hypersensitivity
reaction to the anti-HIV drug abacavir. In the absence of genetic
prescreening, hypersensitivity aects ~6% of patients and can be
life-threatening with repeated dosing. We provide recommenda-
tions (updated periodically at http://www. for the
use of abacavir based on HLA-B genotype.
e purpose of this guideline is to provide information that
will allow the interpretation of clinical HLA-B genotype tests
so that the results can be used to guide the use of abacavir for
the treatment of HIV. Detailed guidelines regarding selection of
appropriate antiretroviral therapy based on patient demograph-
ics and clinical measurements, viral resistance testing, and cost-
eectiveness analyses, are beyond the scope of this article but are
available at Clinical Pharmacogenetics
Implementation Consortium (CPIC) guidelines are published
and updated periodically on to reect
new developments in the eld.
A systematic search of the literature focused on HLA-B genotype
and abacavir use (see Supplementary Data online); reviews
were relied on to summarize much of the earlier literature.
HLA-B is a member of the major histocompatibility complex
(MHC) gene family located on chromosome 6, which consists
of class I, II, and III subgroups. e HLA-B gene product is
a class I HLA molecule that must heterodimerize with β-2
microglobulin to form a functional complex at the cell surface.
HLA class I molecules are expressed on almost all cells and
are responsible for presenting peptides to immune cells. Cells
in the body are constantly producing new proteins, breaking
down old proteins, and recycling the breakdown products into
new proteins. However, some of these peptides are attached to
MHC molecules instead, and are tracked to the cell surface.
In a typical cell, the peptides presented are the breakdown
products of normal proteins and are recognized by immune
cells as such (i.e., self”). However, if a cell becomes infected by
a pathogen, some of the peptides presented will have resulted
from the breakdown of foreign proteins and will be recognized
as “non-self,triggering an immune response against the anti-
gen. MHC molecules are also critical in the eld of transplant
immunology, where careful HLA matching between donor
and recipient minimizes transplant rejection.
In addition,
in rare cases, some pharmaceuticals are capable of producing
immune-mediated hypersensitivity reactions through interac-
tions with MHC molecules, although the exact mechanism of
these interactions remains unclear. Some suggest that these
drugs may function as haptens that irreversibly bind to the
peptides presented to immune cells, causing them to attack
the peptide-hapten conjugate.
Another theory suggests that
these compounds might interact directly with MHC molecules
or T-cell receptors, leading to T-cell activation.
Because of the need to present a wide variety of peptides for
immune recognition, HLA genes are both numerous and highly
Other than in identical twins, the probability is
extremely small that two individuals will be an exact HLA match
across all loci. More than 1,500 HLA-B alleles have been identi-
ed, but the guidelines we present here specically discuss only
the HLA-B*57:01 allele as it relates to abacavir hypersensitivity
reaction (HSR).
Clinical Pharmacogenetics Implementation
Consortium Guidelines for HLA-B Genotype and
Abacavir Dosing
MA Martin
, TE Klein
, BJ Dong
, M Pirmohamed
, DW Haas
and DL Kroetz
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA;
Department of Genetics, Stanford
University, Stanford, California, USA;
Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, California, USA;
Department of
Pharmacology, University of Liverpool, Liverpool, UK;
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA;
Department of Pharmacology,
Vanderbilt University, Nashville, Tennessee, USA;
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
Correspondence: DL Kroetz (
Received 7 October 2011; accepted 15 December 2011; advance online publication 29 February 2012. doi:10.1038/clpt.2011.355
Page 1
Genetic test interpretation
Clinical genotyping tests are available to identify HLA-B alleles.
It is preferable to perform only specic tests for HLA-B*57:01
because more extensive HLA genotyping does not add clinically
useful information with regard to abacavir treatment. Unlike
many other pharmacogenetic associations, HLA-B allele status
has no eect on abacavir pharmacodynamics or pharmacoki-
netics; it only inuences the likelihood that an HSR will occur.
Furthermore, given the codominant expression of HLA-B, geno-
typing results are either “positive” (HLA-B*57:01 being present
in one or both copies of the HLA-B gene) or “negative(no
copies of HLA-B*57:01 are present), with no intermediate phe-
notype. e assignment of the likely HLA-B phenotype, based
on allele diplotypes, is summarized in Ta ble 1. e prevalence
pattern of HLA-B alleles varies signicantly by population, and
it has been extensively studied in geographically, racially, and
ethnically diverse groups (see Supplementary Tables S1 and S2
online). e frequency of the HLA-B*57:01 allele is lowest in
African and Asian populations and is totally absent in some
African populations as well as in the Japanese. In European
populations, this allele is relatively common, with a frequency
of 6–7%. e highest frequency of HLA-B*57:01 is reported in
Southwest Asian populations, where up to 20% of the popula-
tion are carriers.
Available genetic test options
Several methods of HLA-B genotyping are commercially avail-
able. e Supplementary Data online and the Pharmacogenetic
Tests section of PharmGKB (
forScienticUsers/pharmacogenomic_tests.jsp) contain more
information on available clinical testing options.
Incidental findings
Variations in HLA-B have been associated with several autoim-
mune conditions. For example, the presence of the HLA-B27
type is associated with development of ankylosing spondylitis,
which commonly occurs alongside other inammatory condi-
tions, including uveitis, psoriasis, and inammatory bowel dis-
ease. Despite decades of research, the causative mechanism for
this is still unclear.
Several variants in HLA-B have been associated with other
adverse drug reaction phenotypes. Patients with the HLA-B*15:02
genotype are at increased risk of developing Stevens–Johnson
syndrome from treatment with carbamazepine,
whereas HLA-
B*58:01 is associated with an increased risk of severe cutaneous
adverse reactions in response to allopurinol.
In addition to abacavir HSR, HLA-B*57:01 has previously been
linked to ucloxacillin-induced liver injury.
Although the rela-
tive risk of liver injury was more than 40 times greater in HLA-
B*57:01-positive patients than in HLA-B*57:01-negative ones,
the incidence of ucloxacillin hepatotoxicity is rare (<1 in 5,000),
signicantly less than that of abacavir HSR; therefore routine
screening for HLA-B*57:01 is not done to assess susceptibility
to ucloxacillin-induced liver injury.
HLA-B*57:01 has also been shown to be overrepresented in
HIV long-term nonprogressors,
the small group of HIV-
positive patients in whom, despite the absence of antiretroviral
therapy, the condition does not progress to AIDS. is suggests
that HLA-B*57:01 in some way confers a host immune response
that is better able to control the virus. In addition, HLA-B*57:01
has been associated with a lower viral load set point (i.e., the
amount of viral RNA detectable in blood during the asympto-
matic period of HIV) in Caucasians;
similar associations, with
lower viral loads, have been observed in African Americans with
the closely related allele HLA-B*57:03.
Abacavir is a nucleoside reverse transcriptase inhibitor indi-
cated for the treatment of HIV infection, in combination with
other medications, as part of highly active antiretroviral therapy.
Abacavir competitively inhibits viral reverse transcriptase, sup-
pressing HIVs ability to convert its RNA genome into DNA
before insertion into a host cell’s genome. It is commercially
available as a single agent (Ziagen) or coformulated as a xed-
dose combination with other nucleoside reverse transcriptase
inhibitors, lamivudine (Epzicom/Kivexa) and lamivudine/zido-
vudine (Trizivir). As compared with a tenofovir-based highly
active antiretroviral therapy regimen, an abacavir-based one
showed a signicantly shorter time to virologic failure and also
a shorter time to rst adverse event in patients with baseline
viral loads >100,000 copies/ml
but showed no dierences in
virologic failure rates in patients with lower baseline viral loads.
Abacavir received signicant attention aer the report of an asso-
ciation of the drug with an increased risk of myocardial infarc-
as compared with other nucleoside reverse transcriptase
inhibitors; however, subsequent analyses,
including a meta-
analysis conducted by the US Food and Drug Administration
(FDA), have failed to show any such association.
Although abacavir is generally well tolerated, ~5–8% of
patients experience HSR during the rst 6 weeks of treatment
if genetic prescreening is not performed. Symptoms of HSR
increase in severity over time if the drug is continued despite
the progressive symptoms. Symptoms of an HSR include at
least two of the following: fever, rash, gastrointestinal symp-
toms (e.g., nausea, vomiting, abdominal pain), fatigue, cough,
and dyspnea. Suspicion of an HSR warrants immediate discon-
tinuation of abacavir. If the symptoms of clinically diagnosed
Table 1 Assignment of likely HLA-B phenotypes based on
Likely phenotype Genotypes
Examples of
Very low risk of
hypersensitivity (constitutes
of patients)
Absence of *57:01 alleles
(reported as “negative
on a genotyping test)
High risk of hypersensitivity
(~6% of patients)
Presence of at least one
*57:01 allele (reported as
“positive” on a genotyping
HLA-B, human leukocyte antigen B.
See Supplementary Data online for estimates of genotype frequencies among
different ethnic/geographic groups.
*X = any HLA-B genotype other than *57:01.
Page 2
736 VOLUME 91 NUMBER 4 | APRIL 2012 |
HSR resolve aer discontinuation of abacavir, drug rechallenge
is contraindicated because immediate and life-threatening reac-
tions, including anaphylaxis and even fatalities, can occur.
addition, an allergy to abacavir should be noted in the patient’s
medical record. Previous data have shown that peripheral blood
mononuclear cells from hypersensitive patients have a detect-
able immune response when cultured with abacavir in vitro,
including increased expression of interferon-γ, tumor necrosis
factor-α, and other inammatory cytokines, showing a clear role
of the immune system in mediating abacavir HSR.
Linking genetic variability to variability in drug-related
There is substantial evidence linking the presence of the
HLA-B*57:01 genotype with phenotypic variability (see
Supplementary Table S3 online). The application of a
grading system to the evidence linking genotypic variability to
phenotypic variability indicates a high quality of evidence in the
majority of cases (see Supplementary Table S3). e evidence
described below and in Supplementary Table S3 provides the
basis for the recommendations in Figure 1 and Table 2.
In 2002, two independent research groups reported the initial
association between HLA-B*57:01 and abacavir HSR
cohort and case–control designs. e association was replicated
in a UK population in 2004.
However, the results were not
broadly generalizable because the populations studied were pre-
dominantly white males. Nevertheless, given the strength of the
observed association, some centers began implementing pro-
spective screening of HLA-B*57:01 in all HIV-positive patients
to exclude HLA-B*57:01 positivity before starting abacavir.
is approach led to signicant reductions in the incidence of
ese studies, along with the retrospective SHAPE
found that HLA-B*57:01 was also predictive of HSR in
females and in African Americans.
Moreover, the results of PREDICT-1, the rst double-blind,
prospective, randomized trial of a genetic test to reduce adverse
drug events, showed that genetic prescreening for HLA-B*57:01
resulted in no immunologically conrmed HSR events among
HLA-B*57:01-negative patients in the genetic testing arm,
a 2.7% incidence of immunologically conrmed HSR among
842 unscreened patients in the standard-of-care control arm.
e results of PREDICT-1 and the existing body of evidence
prompted the FDA to implement a black box warning in 2008
about the high risk of HLA-B*57:01-associated HSR. e FDA
recommended that all patients be screened before being treated
with abacavir (including those who had previously tolerated the
drug and were being restarted on the therapy) and that abacavir
not be initiated in carriers of HLA-B*57:01. Abacavir is one of a
limited number of drugs for which the FDA has recommended
genetic testing prior to use, and it remains one of the best exam-
ples to date of pharmacogenetics being integrated into routine
medical practice.
Therapeutic recommendations
We agree with others
that HLA-B*57:01 screening should
be performed in all abacavir-naive individuals before initiation
of abacavir-containing therapy (see Tabl e 2); this is consistent
with the recommendations of the FDA, the US Department
of Health and Human Services, and the European Medicines
Agency. In abacavir-naive individuals who are HLA-B*57:01-
positive, abacavir is not recommended and should be consid-
ered only under exceptional circumstances when the potential
benet, based on resistance patterns and treatment history, out-
weighs the risk. HLA-B*57:01 genotyping is widely available in
the developed world and is considered the standard of care prior
to initiating abacavir. Where HLA-B*57:01 genotyping is not
Patient being
considered for
genetic test
Do not prescribe
abacavir. Select an
alternative agent.
Does the patient
have signs and
symptoms of HSR?
Ye s
abacavir and switch
to alternative agent.
Continue abacavir.
Initiate abacavir
therapy and
monitor for HSR.
Figure 1 Treatment algorithm for clinical use of abacavir based on HLA-
B*57:01 genotype. HLA-B, human leukocyte antigen B; HSR, abacavir
hypersensitivity reaction.
Table 2 Recommended therapeutic use of abacavir in relation to
HLA-B genotype
for phenotypic
for abacavir
Classification of
Noncarrier of
Low or reduced
risk of abacavir
Use abacavir per
standard dosing
Carrier of
increased risk
of abacavir
Abacavir is not
HLA-B, human leukocyte antigen B.
Rating scheme described in Supplementary Data online.
Page 3
clinically available (such as in resource-limited settings), some
have advocated initiating abacavir, provided there is appropri-
ate clinical monitoring and patient counseling about the signs
and symptoms of HSR, although this remains at the clinicians
ere is some debate among clinicians regarding whether
HLA-B*57:01 testing is necessary in patients who had previously
tolerated abacavir chronically, discontinued its use for reasons
other than HSR, and are now planning to resume abacavir. e
presence of HLA-B*57:01 has a positive predictive value of ~50%
for immunologically conrmed hypersensitivity,
that some HLA-B*57:01-positive individuals can be, and have
been, safely treated with abacavir. However, we were unable to
nd any data to show that HLA-B*57:01-positive individuals
with previous, safe exposure to abacavir had zero risk of HSR
upon re-exposure. Although there are isolated case reports
of previously asymptomatic patients developing a hypersen-
sitivity-like reaction aer restarting abacavir,
there were
confounding circumstances. Many of the patients had compli-
cating concomitant illnesses that could have masked an HSR
during initial abacavir therapy, and none were immunologi-
cally conrmed, making the case reports dicult to interpret.
Furthermore, most of these case reports precede the availability
of HLA-B*57:01 genetic testing, making it impossible to deter-
mine from the published data whether there could be a risk of
HSR upon re-exposure to abacavir in previously asymptomatic
HLA-B*57:01-positive patients.
In addition, there may also exist a small group of patients
who have been on chronic abacavir therapy since before the
introduction of HLA-B*57:01 genotyping. Given that virtually
all abacavir HSR events occur within the rst several weeks
of therapy, and that ~50% of HLA-B*57:01 carriers can safely
take abacavir, we were unable to nd any evidence to suggest
that HLA-B*57:01-positive individuals on current, long-term,
uninterrupted abacavir therapy are at risk of developing HSR.
Existing clinical guidelines
have a blanket recommendation
that all HLA-B*57:01-positive individuals should avoid abacavir,
regardless of patient history. Although HLA-B*57:01 genotyp-
ing has proven utility in signicantly reducing the incidence
of both clinically diagnosed and immunologically conrmed
in patients being newly considered for
abacavir therapy, the connection between HLA-B*57:01 geno-
type and risk of HSR in patients with previous asymptomatic
abacavir use is less clear.
Recommendations for incidental findings
Although other variants in HLA-B are associated with autoim-
mune diseases and drug response phenotypes, they have not
been associated with abacavir HSR.
Other considerations
Abacavir skin patch testing may be performed after a case
of clinically diagnosed HSR to determine whether it can be
immunologically conrmed. At this time, skin patch testing is
an investigational procedure, and the results should be inter-
preted only by an experienced immunologist. More details on
skin patch testing can be found in the Supplementary Materials
and Methods online.
Potential benefits and risks for the patient
A clear benet of HLA-B*57:01 testing is that it leads to a reduc-
tion in the incidence of abacavir HSR by identifying patients at
signicant risk so that alternative antiretroviral therapy can be
prescribed for them. Importantly, a number of eective and safe
antiretrovirals are available that can be substituted for abacavir
in patients carrying this risk-related allele. HLA-B*57:01s high
negative predictive value (>99%)
shows that it is extremely
effective in identifying those at risk of immunologically
conrmed hypersensitivity to abacavir. A potential problem
would be an error in genotyping or in reporting a genotype.
is could result in high-risk patients mistakenly being given
abacavir and potentially having an HSR. However, given that
patients testing negative for HLA-B*57:01 also have a 3% risk
of developing a clinically diagnosed HSR, standard practice
would include patient counseling and careful monitoring for
signs and symptoms of an HSR. Given the lifelong nature of
genotype results, an error in genotyping may also have a broader
adverse impact on a patients health care if other associations
with HLA-B*57:01 are found in the future.
Caveats: appropriate use and/or potential misuse of
genetic tests
e positive predictive value of HLA-B*57:01 genotyping is
~50%, which means that a signicant number of patients will
be denied abacavir on the basis of their genotyping results even
though they would have been able to take abacavir without
experiencing an HSR. ere is currently no way to know a
priori which HLA-B*57:01 carriers are and which are not likely
to experience HSRs, although new genetic risk factors may be
found in the future. Given the potential seriousness of HSRs,
the moderate positive predictive value is greatly outweighed
by the very high negative predictive value of HLA-B*57:01
HLA-B*57:01 is not predictive of any other adverse reactions
a patient may experience while on abacavir treatment, nor does
it predict whether abacavir will be eective in treating a patients
HIV. In addition, genotyping is not a replacement for appropri-
ate patient education and clinical monitoring for the signs and
symptoms of hypersensitivity. e development of signs and
symptoms of an HSR warrants that serious consideration be
given to discontinuing abacavir, regardless of the HLA-B geno-
typing results.
CPIC guidelines reect expert consensus based on clinical evi-
dence and peer-reviewed literature available at the time they
are written and are intended only to assist clinicians in decision
making and to identify questions for further research. New evi-
dence may have emerged since the time a guideline was submit-
ted for publication. Guidelines are limited in scope and are not
applicable to interventions or diseases not specically identied.
Guidelines do not account for all variations among individual
Page 4
738 VOLUME 91 NUMBER 4 | APRIL 2012 |
patients and cannot be considered inclusive of all proper meth-
ods of care or exclusive of other treatments. It remains the
responsibility of the health-care provider to determine the best
course of treatment for the patient. Adherence to any guideline
is voluntary, with the ultimate determination regarding its appli-
cation to be made solely by the clinician and the patient. CPIC
assumes no responsibility for any injury to persons or damage
to property related to any use of CPIC’s guidelines, or for any
errors or omissions.
SUPPLEMENTARY MATERIAL is linked to the online version of the paper at
We acknowledge the critical input of members of the Clinical
Pharmacogenetics Implementation Consortium of the Pharmacogenomics
Research Network, funded by the National Institutes of Health (NIH). This
work was funded by NIH grants GM61390 and GM61374.
The authors declared no conflict of interest.
© 2012 American Society for Clinical Pharmacology and Therapeutics
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    • "International HapMap Project and Human Genome Project) have produced a wealth of data and repositories in this field. Several areas of medicine have already been influenced by pharmacogenetics, for example warfarin dosing (Pirmohamed et al., 2013), predicting responders to interferon-α in hepatitis C (Pirmohamed, 2011) and identification of individuals at risk of abacavir hypersensitivity reaction (Martin et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Alcohol dependence is a common disorder in many societies worldwide, and remains difficult to identify and treat. It is also a risk factor for many secondary non-communicable diseases. Pharmacotherapy is one available treatment option, but appears to be underutilised in practice. Major barriers to use of medications in this area include lack of clinical guidance and questionable efficacy. However, for each medication there appears to be a subpopulation that responds positively, and understanding the moderating factors to treatment efficacy is an important research goal. Thus, this review provides a narrative regarding potential stratification techniques in pharmacological treatment of alcohol dependence, with a specific focus on typologies and pharmacogenetics. In addition, we discuss the basic background of stratified medicine and recent studies on genetic predisposition to alcohol dependence. A growing repository of data exists for both approved and non-approved pharmacotherapies, but failure to replicate findings, inadequate sample sizes, and insufficient funding has resulted in a translational gap. Implementing evidence-based stratified/personalised therapy and identifying new therapeutic agents may lead to improved clinical outcomes and reduced financial burden. Despite some promising findings to date, much work is still required. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Pharmacology [?] Therapeutics
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    • "It remains unclear if association to response will necessarily translate into improved outcomes, and there has been a reluctance to apply these findings clinically. Other medical disciplines have increasingly demonstrated the utility of personalized medicine [7] with PGT showing advantages in warfarin dosing [8] , thiopurine myelosuppression in leukemia [9,10] and abacavir hypersensitivity in HIV [11,12]. However, these fields are experiencing similar inertia, even in cases where the supporting evidence is strong [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Bipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients. Discussion A number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD. Summary Based upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD.
    Full-text · Article · May 2014 · BMC Medicine
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    • "[2] [3] [4] [5] [6] [7] [8] [9] [10] "
    [Show abstract] [Hide abstract] ABSTRACT: The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.
    Full-text · Article · Jan 2014 · Current Drug Metabolism
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