Download The Clinical Utility of Pharmacogenetic Tests in HIV Therapy

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The Clinical Utility of Pharmacogenetic Tests in HIV Therapy
David Boettiger
Erasmus MC Rotterdam, Department of Virology
The introduction of HAART has had a remarkably positive impact on HIV patient survival.
However individual genetic variability can significantly affect patient response to drugs. A
number of associations between genotype and antiretroviral response have been identified,
none more important than that of HLA-B*5701 and abacavir hypersensitivity. The abacavir
example highlights the quality of evidence required for a pharmacogenetic test to be
accepted into clinical practice. This review summarizes the current, confirmed
pharmacogenetic associations in HIV therapy and provides an assessment of their clinical
utility based on the evidence to date. True individualization of antiretroviral treatment
remains a distant hope. Nevertheless, with careful consideration of the requirements for a
pharmacogenetic test to gain acceptance into clinical practice and advanced scientific
techniques we may soon see rapid development in the utilization of pharmacogenetics in HIV
therapy.
Keywords
HIV, HAART, antiretroviral, pharmacogenetics, pharmacogenetic testing, abacavir
Introduction
Since the introduction of combined drug treatment for HIV in the form of Highly Active Antiretroviral
Therapy (HAART) patient survival has improved enormously. When HIV/AIDS was first recognized in
the early 1980s it typically killed patients within 1-2 years. Now, newly infected patients in the
developed world can generally expect to live at least another 30 years.1
The first drug recognized to be efficacious against HIV was the nucleotide reverse transcriptase
inhibitor, zidovudine.2, 3 Unfortunately, monotherapy with zidovudine and lack of experience with HIV
led to the rapid emergence of resistance.4 Since then numerous compounds have been added to the
nucleotide/side reverse transcriptase (NRTI) drug class and several other antiretroviral classes
developed. With a current first-line HAART regimen, typically consisting of two NRTIs and a nonnucleotide reverse transcriptase inhibitor (NNRTI) or protease inhibitor, patients can achieve an
undetectable viral load and almost normal CD4 cell level, as well as dramatically slow the emergence
of HIV drug resistance. The recent introduction of CCR5 inhibitors and integrase inhibitors has also
provided additional second- and third-line treatment options.
Current treatment guidelines for HIV are based largely on the efficacy, cost, availability and toxicity of
antiretrovirals, as well as the clinical experience with their use.5-7 While these are logical parameters
on which to base such guidelines, their ‘generizability’ to individuals is limited. For example, a new
patient may reasonably be prescribed an affordable and available first-line antiretroviral, which is
known to be effective in 90% of patients and cause serious nephrotoxicity in only 0.5% of users.
Whilst an appropriate choice for most, there remains a 10% chance the drug will not be efficacious,
and it is impossible to distinguish whether the patient is likely to be one of the unlucky few to suffer
drug-induced nephrotoxicity.
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A range of factors may contribute to variability in antiretroviral response. Age, gender, ethnicity, drug
interactions, drug resistance, concomitant disease states, pregnancy and individual genetic variation
are all known to influence pharmacodynamics. Pharmacogenetics examines the effect of specific
genetic variants on drug response. To date, most pharmacogenetic studies have evaluated
associations as a function of variation in the genes encoding proteins important in pharmacokinetics
and/or drug toxicity (i.e. transport proteins, metabolizing enzymes, and immune response proteins).
Pharmacogenetic research ultimately aims to individualize patient treatment. Pre-treatment
screening for genetic variants known to influence the efficacy or toxicity of a drug may lead to more
elaborate treatment guidelines that prevent unnecessary side effects or regimen failure. The best
example of this in HIV medicine is the pharmacogenetic test for Human Leukocyte Antigen (HLA)B*5701 to avoid abacavir toxicity. Abacavir causes a severe, potentially life-threatening
hypersensitivity reaction in a small percentage of users. Based on evidence that certain HLA
genotypes were more prevalent in these patients,8-10 various authors hypothesized (and later
confirmed) that genotypic testing could prospectively identify those most likely to succumb to
abacavir hypersensitivity.11-14
Despite the large number of approved antiretrovirals available, abacavir provides the only current
example of a clinically useful pharmacogenetic test in HIV treatment. Other clear genotypephenotype links exist, however research must prove a genetic test is clinically relevant, affordable,
convenient and acceptable to patients and healthcare workers before it will be implemented into
clinical practice. This review summarizes the confirmed, clinically important and potentially
important pharmacogenetic associations identified by HIV research to date, and assesses their clinical
utility based on the current evidence. ‘Confirmed’ associations are defined here as those involving a
particular gene, single nucleotide polymorphism, allele or haplotype with at least two, independent
supporting studies and minimal or no conflicting evidence. ‘Clinically important and potentially
important’ associations are defined here as those known or suspected to be related to significant
improvement or inhibition of drug efficacy, or significant increase or decrease in the likelihood of an
adverse event, in a large number of patients. For a thorough list of recognized, suspected and
controversial associations the reader is directed to the HIV Pharmacogenomics website (www.hivpharmacogenomics.org).15
Search Strategy
PubMed and Embase were searched for relevant literature. Appendix 1 is a list of the keywords used
in this search. Associations were only considered in detail if current evidence indicated they were of
clinical significance or likely to be of clinical significance. If a reported association was not supported
by other independent pharmacogenetic or general population data, or there existed any more than
minor contrary evidence of the association, it was not considered in detail. Included studies needed
to evaluate a pharmacogenetic association in HIV positive patients using at least one antiretroviral
drug. Studies were required to evaluate at least one pharmacogenetic association involving a specific
gene but not necessarily a specific mutation in that gene. All study designs were considered for
inclusion. Review articles, articles not written in English, studies in non-human subjects and in vitro
experiments were excluded.
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The reference lists of articles selected from the abovementioned procedure were individually
screened for additional studies of relevance. The HIV pharmacogenetics website’s list of
pharmacogenetic associations was also searched for studies not already captured.15
Introducing a Pharmacogenetic Test into Clinical Practice
Box 1 details the requirements of a pharmacogenetic test before it will be incorporated into practice.
Importantly, evidence and opinion must clearly favor the clinical relevance of such a test before cost
effectiveness is evaluated, a robust assay and reporting system developed, patient and health care
worker education initiated, and finally, recommendation given by clinical guidelines.
 CLINICALLY RELEVANT
High quality data must show a clear pharmacogenetic association and that patients, preferably
from a wide range of ethnic backgrounds, will gain significant benefit from a test based on this
association.
 COST EFFECTIVE
The cost of testing must be outweighed by the benefit it will provide.
 ROBUST ASSAY
The test assay must exhibit acceptable sensitivity and specificity.
 QUICK SIMPLE REPORT
The test must generate an easily interpretable report in a timely manner.
 SUFFICIENT EDUCATION
Patients and health care professionals need to be aware of testing implications and limitations.
 GUIDELINE RECOMMENDATION
Guideline recommendation will ensure the test is incorporated into local protocol.
Box 1. Requirements for introduction of a pharmacogenetic test into clinical practice
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
NRTIs are structurally similar to natural nucleoside/nucleotides used in nucleic acid synthesis only
they lack a 3’ hydroxyl group. After phosphorylation NRTIs are incorporated by HIV reverse
transcriptase into viral DNA and effectively terminate DNA elongation as 5’ to 3’ phosphodiester
linkage can no longer occur. Hepatic glucuronidation is thought the main metabolic pathway of
zidovudine, while lamivudine and tenofovir are renally excreted virtually unchanged. Abacavir is
predominantly metabolized in the liver by alcohol dehydrogenase and glucoronidation. Two
members of the ATP-binding cassette super family, multidrug resistance protein (MRP) 4 and breast
cancer related protein, are important NRTI transport proteins that regulate intracellular drug
concentration. The immune response protein, HLA, plays a strong role in the hypersensitivity reaction
occasionally seen with abacavir use.
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Abacavir hypersensitivity (HLA-B*5701 & HCP5 T335G)
Abacavir is a well-tolerated antiretroviral that appears to exhibit similar or slightly inferior efficacy
compared to more frequently used NRTIs such as tenofovir and emtricitabine.16-19 The main
treatment limiting toxicity associated with abacavir is a hypersensitivity reaction that typically occurs
during the first 6 weeks of treatment in approximately 5% of patients.20 It is characterized by nonspecific symptoms, such as fever, rash, and gastrointestinal and respiratory manifestations, which
make clinical diagnosis difficult.20 Symptoms usually subside within 24 hours of ceasing the drug
however re-challenge is contra-indicated as it can result in severe morbidity or death.21
The recognition that abacavir hypersensitivity reaction (AHR) occurs in few individuals shortly after
initiating treatment and that those who do not develop the reaction remain at low risk despite
continued therapy led researchers to believe genetic susceptibility may be involved. Early work
supported this theory by demonstrating a familial connection to AHR,22 as well as an association with
Caucasians, but not blacks.10 This was followed by two further studies independently establishing an
association between AHR and the major histocompatibility complex class I allele, HLA-B*5701.8, 9
Although the precise mechanism remains unknown, biological evidence that AHR is mediated by HLAB*5701 restricted CD8+ lymphocytes came from cellular and ex vivo studies showing strong tumour
necrosis factor-α and interferon-γ responses, and CD8+ proliferation after ex vivo exposure to
abacavir.23, 24 The increasing body of evidence supporting the relationship between HLA-B*5701 and
AHR encouraged observational research assessing the utility of HLA-B*5701 screening in clinical
practice.11, 14 The positive results gleamed from this work necessitated a randomized trial.
The PREDICT-1 study was a randomized, double-blind, controlled trial that enrolled 1956 HIV infected
patients of various (mainly Caucasian) ethnic backgrounds.13 Both HLA-B*5701 negative and
unscreened (control) patients were treated with an abacavir regimen. To confirm a diagnosis of AHR,
patients were exposed to an epicutaneous patch test. Screening prevented all immunologically
confirmed AHR (0% screened group vs. 2.7% control group), and significantly reduced clinically
diagnosed cases (3.4% screened group vs. 7.8% control group). The authors therefore concluded that
a pharmacogenetic test for HLA-B*5701 prevents AHR.
Further research confirmed the feasibility of introducing HLA-B*5701 screening into clinical practice.
The results from Saag et al (2008)12 showed that HLA-B*5701 screening is a sensitive and specific
marker for immunologically confirmed AHR in black and white populations, despite observing only a
very small number of reactions in black patients (n=5). Hammond et al (2007)25 demonstrated that
sequence specific PCR amplification could provide similarly accurate results to the more expensive
and laborious full high resolution HLA typing used to prove the clinical relevance of HLA-B*5701
screening.
Two studies have indicated the cost-effectiveness of HLA-B*5701 testing.26, 27 The latest of these
applied data from PREDICT-1 to simulate a cohort of patients receiving HIV therapy.26 This allowed
the authors to perform a cost-effectiveness assessment of HLA-B*5701 testing for guiding selection
of first-line HIV regimens in the United States. First-line abacavir, lamivudine, and efavirenz without
prior HLAB*5701 testing was compared to the same regimen with prior HLA-B*5701 testing and a
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first-line regimen of tenofovir, emtricitabine and efavirenz. Abacavir-based treatment with HLAB*5701 testing was estimated to cost $36,700 per quality adjusted life year (QALY) gained when
compared to no testing, below the commonly accepted thresholds in the United States of $50,000$100,000/QALY.26 Initiating treatment with a tenofovir-based regimen increased costs without
improving QALYs. Interestingly, especially given recent data indicating abacavir-based HAART exhibits
inferior efficacy to tenofovir-based therapy16, 17, HLA-B*5701 testing remained the preferred strategy
only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based
treatment. Results were also sensitive to the cost of HLA-B*5701 testing and the prevalence of
HLA*B5701.
Since 2008, US and UK guidelines have indicated that abacavir should not be used without prior HLAB*5701 screening and should be avoided in patients that test positive.6, 28 Importantly, both
guidelines warn that HLA-B*5701 negative patients may rarely experience AHR and hence it remains
appropriate to monitor for signs of abacavir hypersensitivity after genetic testing. The most recent
World Health Organization guidelines on the other hand refrain from commenting on HLA-B*5701
testing, instead stating that abacavir adds additional cost and complexity that adds serious constraint
to its use in first-line regimens and prevents its recommendation as a preferred second-line agent.5
This highlights an important weakness of pharmacogenetic testing. Despite the clear benefit of HLAB*5701 testing, it adds an additional requirement to prescribing. Combined with data from
randomized controlled trials indicating the inferior efficacy16, 17 and cardiovascular safety19 of
abacavir compared to other NRTIs, it makes for an unattractive option to physicians.
Interestingly, new research into AHR has discovered that the HLA complex P5 (HCP5) single
nucleotide polymorphism, T335G, is an accurate surrogate marker of HLA-B*5701.29, 30 When
compared with HLA-B*5701 testing in a study of 245 HIV infected patients, HCP5 testing showed a
93% positive predictive value and 100% negative predictive value.30 As genotyping HCP5 T335G is
cheaper and easier than HLA-B*5701 testing, further confirmation of the sensitivity and specificity of
this assay may prove it to be a good alternative for predicting AHR.
Tenofovir-associated renal tubulopathy (MRP2)
Tenofovir exhibits strong antiretroviral efficacy, a good safety profile and a long half-life that permits
once-daily dosing. Unsurprisingly therefore, it is a very popular drug in first-line HIV treatment.
Although randomized controlled trials in HIV infected patients indicated tenofovir exhibits good renal
safety,31-34 rare cases of renal tubular dysfunction have been reported in tenofovir users which raises
concern about long-term use of the drug.35-41 Tenofovir undergoes extensive renal clearance by a
combination of glomerular filtration and active tubular secretion. It is taken up at the proximal tubule
basolateral membrane by human organic anion transporter 1 and transported into the urine by
MRP4, and possibly MRP2, mediated cellular efflux at the apical membrane.42 The mechanism
underlying tenofovir-associated renal tubulopathy remains undetermined however it could be that
dysfunctional transport protein function leads to tenofovir accumulation in renal proximal tubular
cells and subsequent toxicity.
Retrospective analysis has shown little association between genetic variants of human organic anion
transporter 1 and tenofovir pharmacokinetics suggesting they do not contribute to tenofovir-
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associated renal toxicity.43 On the other hand, a small case-control study by Izzedine et al (2006)44
found that the G1249A single nucleotide polymorphism and four polymorphism haplotype, CATC, of
the ABCC2 gene (encoding MRP2) are both associated with tenofovir-induced renal tubulopathy. In
support of this finding, a recent study by Rodriguez-Novoa et al (2009)45 found that in a population of
tenofovir treated HIV patients (n=115), the percentage of patients with tenofovir-associated renal
tubulopathy (n=19) was higher among those with genotype CC at position 24 of ABCC2 than among
those with genotypes CT or TT (24% vs. 6%). This preliminary work suggests a pharmacogenetic test
involving the ABCC2 gene may be useful for preventing tenofovir use in those susceptible to
developing renal tubulopathy. However more convincing research is required to confirm this
association, define a specific variant of the ABCC2 gene involved in this association, and to elucidate
the likely mechanism/s involved.
NRTI-associated pancreatitis (CFTR & SPINK-1)
Pancreatitis is a known adverse event of NRTIs, particularly didanosine.46 Cystic fibrosis
transmembrane regulator (CFTR) and serine protease inhibitor kazal-1 (SPINK-1) variants have been
associated with chronic and idiopathic pancreatitis in the general population.47-49 The mechanism/s
by which CFTR mutation may lead to pancreatitis has not been established. SPINK-1 is a potent
protease inhibitor which might protect against pancreatitis by preventing activation of the pancreatic
digestive enzyme cascade.50 Polymorphisms in SPINK-1 could therefore inhibit this function.
Felley et al (2004)51 conducted a study in HIV infected patients to compare the frequency of various
CFTR mutations and the SPINK-1 polymorphism, N34S, in patients with hyperamylasemia and
matched controls. Ten patients were diagnosed with acute pancreatitis, four of whom had CFTR
mutations or the SPINK-1 polymorphism (40%) compared with 9 of 90 controls or asymptomatic
hyperamylasemia patients (10%). This study indicated that CFTR mutations and the N34S
polymorphism in SPINK-1 may further increase susceptibility to pancreatitis in HIV patients treated
with NRTIs. Currently this association is only supported by data from the general population studies
mentioned above. Furthermore, much larger, higher quality studies are required involving analysis of
CFTR mutations alone, SPINK-1 polymorphism alone, or co-presence of these genetic variants.
NRTI-associated peripheral neuropathy (Mitochondrial haplotypes)
Stavudine and didanosine exhibit numerous serious safety concerns that limit their clinical use.5
Unfortunately, in many resource poor settings stavudine remains a first-line option due to its
availability and affordability. One of the serious toxicities of stavudine and didanosine (and to a lesser
extent other NRTIs) is the development of peripheral neuropathy.52 The mechanism by which NRTIs
cause peripheral neuropathy and other long-term toxicity (such as lipoatrophy, hepatic steatosis and
lactic acidosis) is probably associated with NRTI-induced mitochondrial injury. Although NRTIs
predominantly inhibit viral nucleic acid synthesis, they have also been shown to inhibit mitochondrial
DNA polymerase.53, 54 Mitochondrial DNA depletion and subsequent mitochondrial dysfunction leads
to impaired oxidative phosphorylation and tissue injury.55, 56 Similarities between the clinical
manifestations of inherited mitochondrial DNA diseases and the long-term adverse effects of NRTIs
prompted researchers to look for mitochondrial DNA variants that may explain susceptibility to
peripheral neuropathy among HIV infected patients.
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Combinations of polymorphisms define mitochondrial haplogroups which are found with varying
frequency in different continental populations. Approximately 15% of European descendants express
mitochondrial haplogroup T, which is distinguished by a signature pattern of three polymorphisms,
C7028T, G10398A, and G13368A.57 A 2005 case-control study by Hulgan et al found that among 137
white subjects that received didanosine plus stavudine, 20.8% of those who developed peripheral
neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects.58 The
authors followed this up with a similar study in the same population indicating the single nucleotide
polymorphism, A4917G, found almost exclusively in haplogroup T, was also associated with NRTIinduced peripheral neuropathy.59 Although only confirming the likely importance of mitochondrial
DNA variants rather than any specific haplogroup, a study published this year by Canter et al found
that an African subhaplogroup is also implicated in susceptibility to NRTI-associated peripheral
neuropathy.60 These preliminary findings suggest a genetic test of mitochondrial DNA prior to NRTI
initiation may be able to identify those at risk of peripheral neuropathy.
Non-Nucleoside Reverse Transcriptase Inhibitors
NNRTIs have a strong affinity for a hydrophobic pocket located close to the catalytic domain of HIV
reverse transcriptase. When bound they cause a conformational change in the catalytic site that
blocks the enzymes ability to synthesize DNA. Efavirenz is predominantly metabolized by CYP2B6 and
to a lesser extent by CYP3A4. Nevirapine is predominantly metabolized by CYP2B6 and CYP3A4 with a
minor contribution from CYP3A5. Although some pharmacogenetic studies have implicated the
transmembrane efflux drug transporter, MRP1, as an important protein in the pharmacokinetics of
NNRTIs, this remains controversial.61, 62 Similar to the case for abacavir, HLA proteins appear to be
involved in the hypersensitivity reaction occasionally seen in response to nevirapine.
Nevirapine-associated hypersensitivity (HLA-DRB1*0101 & HLA-Cω8)
Nevirapine is frequently prescribed as part of first-line HAART and for preventing mother-to-child
transmission owing to its good efficacy and affordability. Unfortunately however the NNRTI induces a
potentially fatal hypersensitivity reaction characterized by fever, rash and/or hepatotoxicity in
approximately 5% of users.63 As for abacavir, hypersensitivity to nevirapine usually presents within
the first 6 weeks of treatment and re-challenge after a confirmed reaction is contra-indicated.64
However, nevirapine hypersensitivity seems quite complex as both HLA class I and II alleles have
been implicated in different populations65-68 and the reaction may be dependent on CD4+ cell
count.64
Nevirapine hypersensitivity has been shown to occur more frequently in treatment naïve women and
men with a CD4+ cell count greater than 250 cells/mm3 and 400 cells/mm3, respectively, whilst low
CD4+ cell count appears to be protective.64 Further, Martin et al (2005)66 identified an association
between nevirapine hepatic or systemic reactions and the HLA-DRB1*0101 allele which was limited
to patients with a CD4+ cell count greater than 25% (of total white cell count). In contrast, this study
also found the occurrence of nevirapine-associated isolated rash was not associated with CD4+ cell
count or HLA-DRB1*0101. A more recent, although poor quality, study based on a French cohort
reported that 83% (5 of 6) of participants presenting with isolated rash were HLA-DRB1*0101
positive versus only 7% (1 of 15) in the nevirapine-tolerant group and that this association was not
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dependent on CD4+ cell count.68 Hence, it appears different mechanisms could be underlying the risk
of nevirapine-associated isolated rash and nevirapine related hepatic reactions. While the role of
HLA-DRB1*0101 in isolated skin reactions to nevirapine is controversial, HLA-DRB1*0101 testing in
conjunction with a CD4+ cell count may be useful for averting nevirapine sensitivity-associated
hepatotoxicity.
In addition to the abovementioned, the class I HLA allele, HLA-Cω8, has also been implicated in
nevirapine hypersensitivity.65, 67 Following a small study showing the association between HLACω8/HLA-B14 haplotype and nevirapine hypersensitivity reaction in a Sardinian population,67 a
similar study was undertaken in a Japanese population in whom the HLA-B14 allele is not present.
Gatanaga et al (2007)65 reported that the frequency of HLA-Cω8-positive patients in the nevirapinehypersensitive group (n=12) was 42%, which was significantly higher than those of the nevirapinetolerant group (10%, n=29) and the general Japanese population (9–14%). Further supporting data is
required to fully determine the clinical significance of this association.
Nevirapine-associated hepatitis (MRP1 C3435T)
As well as causing an immune-mediated hepatic sensitivity reaction in a small percentage of patients,
nevirapine can cause hepatotoxicity in the form of hepatitis and asymptomatic serum transaminase
elevations.63 This reaction mostly occurs within the first 12 weeks of therapy.69 Whilst the paucity of
knowledge on nevirapine transport in hepatocytes makes it difficult to hypothesize the mechanism
by which the drug may cause hepatitis it has been suggested that altered efflux activity in the gut
associated with MRP1 variants may influence disposition of nevirapine and/or its metabolites in a
way that affects intracellular drug concentrations and toxicity.70 It is uncertain whether nevirapine or
efavirenz are substrates for MRP1, however the C3435T polymorphism in MRP1 has been associated
with improved virological outcome in patients using efavirenz-containing regimens. While it does not
confer an amino acid change, C3435T may reduce MRP1 mRNA stability71 or may be linked to other
functional polymorphisms.72
In 2006, two independent studies reported that C3435T in MRP1 reduces the risk of nevirapineassociated hepatotoxicity.70, 73 The larger of these studies (n=161) used data from a randomized,
double-blind trial conducted in South Africa and found that genotypes at MRP1 position 3435 in case
patients and controls were CC in 83% and 67%, CT in 13% and 28%, and TT in 4% and 6%,
respectively.70 Encouragingly, a recently published case-control study in a Mozambique population
concurs with these findings.74 Additional supporting literature is required to determine the clinical
utility of MRP1 C3435T testing for predicting patients (un)likely to develop nevirapine-associated
hepatitis.
Efavirenz and increased plasma levels (CYP2B6 G516T)
Efavirenz exhibits comparable efficacy to nevirapine and is frequently used in first-line HAART despite
its higher cost. It is associated with central nervous system side effects in as many as 50% of users75.
While the milder, more common adverse effects such as dizziness, insomnia, somnolence and
impaired concentration often resolve without intervention within the first 12 weeks of therapy, 76
more severe central toxicities such as psychosis and depression have been reported.77-80 Various
authors have indicated that adverse effects of efavirenz on the central nervous system frequently
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correspond with high drug plasma concentrations.81-84 Efavirenz also exhibits a long half-life and low
genetic barrier to resistance,85, 86 hence high initial plasma levels could effectively lead to extended
monotherapy and rapid development of HIV drug resistance after ceasing a typical 2xNRTI + efavirenz
regimen.82
Dysfunctional CYP2B6, the main metabolizing enzyme of efavirenz, leads to reduced hepatic
clearance of the NNRTI.87 Studies in populations of various ages and ethnicities have repeatedly
shown CYP2B6 G516T to be associated with increased plasma efavirenz levels.85, 86, 88-98 Moreover,
elevated plasma efavirenz concentrations in patients expressing the CYP2B6 G516T genotype have
been associated with central nervous system side effects.80, 93, 99-101 Studies showing a relationship
between CYP2B6 G516T and the development of efavirenz resistance are currently lacking, however
using clinical trial data Ribaudo et al (2006)86 predicted that plasma efavirenz levels would remain
elevated for >21 days in 29% of subjects with the TT genotype.
Taken together, the abovementioned studies imply pharmacogenetic testing of CYP2B6 may help
guide optimal efavirenz dosing. In fact, a recent study out of Japan by Gatanaga et al (2007)102 found
that dose reduction in CYP2B6 C516T carriers resulted in improvement of central nervous system side
effects for 10 of 14 patients, and that a lower starting dose of 400mg could be successfully initiated in
efavirenz-naïve carriers. Despite this, a recent Cochrane review concluded that current data does not
support routine use of therapeutic drug monitoring in patients receiving HAART citing generally poor
uptake of recommendations as one of the likely reasons for this outcome.103
A key limitation to CYP2B6 G516T pharmacogenetic testing is that the mutation does not lead to
increased efavirenz plasma concentrations in all carriers.90, 93, 100 It has also been suggested that
providing G516T heterozygous patients with a lower dose of efavirenz may increase rates of
virological failure possibly due to the slow-metabolizer phenotype protecting against poor
adherence.101 Current research has identified genetic variants of proteins such as MRP1, CYP2A6,
CYP3A4 and uridine diphosphate glucuronosyl-transferase (UGT) 2B7 that can account for some of
the variability in efavirenz plasma concentrations not explained by CYP2B6 mutation.89, 104-107
Formulation of a predictive algorithm that combines the effects of some or all known factors
influencing efavirenz pharmacokinetics could be used to individualize dosing, however more work is
required in this area.
Protease Inhibitors
The cleavage of precursor proteins by protease is essential for assembly of infectious HIV particles.
Inhibition of protease results in the release of structurally disorganized and non-infectious virus.
Protease inhibitors mimic the structure of precursor protein cleavage sites and hence bind and inhibit
the catalytic domain of protease. They act as both substrates and inhibitors of the CYP3A enzymes.
Commonly, protease inhibitors are co-administered with low-dose ritonavir, a protease inhibitor that
potently antagonizes the CYP3A sub-family, to enhance the bioavailability of the primary protease
inhibitor. They are substrates for MRP1 and bind heavily to the plasma proteins, albumin and α1-acid
glycoprotein. Several proteins, especially various apolipoprotein subtypes, are believed to play a role
in the dyslipidemia and insulin resistance known to be associated with protease inhibitor use.
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Atazanavir- & indinavir-associated hyperbilirubinemia (UGT1A1*28)
Atazanavir is one of the preferred ritinovir-boosted protease inhibitors (along with boosted lopinavir)
recommended by the WHO due to its superior safety, affordability and ease of administration
compared to other protease inhibitors.5 Compared with atazanavir, indinavir exhibits similar efficacy,
is not as well tolerated and is more expensive.5 Patients receiving atazanavir or indinavir have an
increased risk of developing unconjugated hyperbilirubinemia. Although reversible and benign, some
patients may develop overt jaundice which can lead to them discontinuing antiretroviral treatment.
The mechanism behind this reaction is probably due to indinavir and/or atazanavir competitively
inhibiting the conjugation of bilirubin by UGT1A1.108, 109
Reduced UGT1A1 activity caused by mutation in the promoter region of the enzyme (UGT1A1*28)
causes Gilberts syndrome, a common condition characterized by elevated bilirubin. Numerous
studies in patients of Caucasian, African and Asian decent have shown a clear association between
the UGT1A1*28 allele and atazanavir and/or indinavir induced hyperbilirubinemia.110-114 In the one
study that looked at the effect of both protease inhibitors in HIV patients, atazanavir increased
average bilirubin levels by 15mmol/L and indinavir increased average bilirubin levels by 8mmol/L.114
UGT1A1*28 homozygosity increased bilirubin levels by an average of 5.2mmol/L. When combined,
67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had ≥2 episodes
of hyperbilirubinemia in the jaundice range versus 7% of those with the wild-type allele and not
receiving either drug.
In addition to the UGT1A1*28 allele, MRP1 variants appear to increase atazanavir plasma levels
(probably due to reduced clearance) and the subsequent risk of developing hyperbilirubinemia.112, 115
Combined genotyping of UGT1A1 and MRP1 prior to atazanavir or indinavir administration may
identify patients most at risk of developing hyperbilirubinemia. Although it is one of the stronger
pharmacogenetic associations in HIV medicine, the benign nature of hyperbilirubinemia may limit the
clinical acceptability of a UGT1A1 ± MRP1 test prior to atazanavir or indinavir treatment.
Protease inhibitor-associated hypertriglyceridemia (ABCA1, APOA5, APOC3, APOE)
Protease inhibitors and other antiretroviral classes are associated with an increased risk of adverse
cardiovascular outcome, mediated at least in part by dyslipidemia.116-118 Antiretroviral-mediated
dyslipidemia may include hypertriglyceridemia, decreased HDL cholesterol, and/or increased LDL
cholesterol.119 Hypertriglyceridemia associated with HIV drug therapy most frequently occurs with
regimens containing ritonavir.117, 120 The mechanism by which protease inhibitors may lead to
hypertriglyceridemia is not known. However, the fact that not all patients develop
hypertriglyceridemia, despite similar protease inhibitor exposure and comparable demographic,
immunologic, and virologic characteristics suggests involvement of a genetic component.
Polymorphisms in genes known to be associated with dyslipidemia in the general population have
been studied to elucidate their effect on lipid regulation in HIV infected patients. Numerous authors
have established that there is an association between various apolipoprotein C3 (APOC3) and
apolipoprotein E (APOE) genotypes and hypertriglyceridemia in patients using a ritonavir-containing
regimen.119, 121-125 In a study of 329 antiretroviral treated, HIV infected patients, Tarr et al (2005)121
found that patients using ritonavir who expressed an unfavorable genotype for both APOC3 and
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APOE had a median plasma triglyceride level of 7.33mmol/L, compared with 3.08mmol/L in the
absence of antiretroviral therapy. Studies have also confirmed an association between genetic
variants of ATP-binding cassette subfamily A (ABCA1) and apolipoprotein A5 (APOA5), and protease
inhibitor-associated hypertriglyceridemia.119, 125
Arnedo et al (2007)119 incorporated these genotypes into a scoring algorithm for evaluating likely
susceptibility to antiretroviral induced dyslipidemia. Patients received a predictive score based on
their composite ABCA1/APOA5/APOC3/APOE/cholesterol ester transferase protein genotype and the
type of antiretroviral therapy they were using (cholesterol ester transferase protein variants have
been implicated in antiretroviral dyslipidemia though this association has not been confirmed)119.
Although this algorithm is yet to be validated in other study populations, it illustrates how clinicians
may someday identify individuals at increased risk of antiretroviral-related hypertriglyceridemia or
dyslipidemia and thereby reduce the risk of atherosclerotic disease in HIV infected patients.
Assessing the Clinical Utility of Pharmacogenetic Associations in HIV Therapy
A growing interest in pharmacogenetics and the potential for individualized therapy has led to the
discovery of a vast number of genotype-drug response associations in HIV therapy. While their
unveiling is of great intrigue to researchers, clinician and patient interest lies primarily with the
potential for pharmacogenetic testing to improve patient outcome.
Table 2 assesses the clinical utility of the confirmed associations discussed above based on the
criteria outlined in Box 1. The assessment of clinical relevance is split into parts, similar to previous
evaluations of pharmacogenetic testing (Table 3).126 The first part assumes a routine
pharmacogenetic test based on the association is available and provides an evaluation of the
strength of evidence to support using this test in practice. The second classifies the clinical
significance of the association based on the severity of the condition involved, as it most frequently
presents. The evaluation of evidence is based on the WHO 2006 assessment of evidence criteria127 in
that each pharmacogenetic test is given a level A (recommended), B (consider), or C (optional)
recommendation followed by a score of I,II, III or IV based on the evidence to support this
recommendation. A score of I indicates high level evidence including at least one randomized
controlled trial with clinical, laboratory or programmatic end-points; II at least one high-quality study
or several adequate studies with clinical, laboratory or programmatic end-points; III observational
cohort data, one or more case-controlled or analytical studies adequately conducted; and the lowest
level of evidence, IV, indicates expert opinion based on evaluation of other evidence. The clinical
significance of each association is given a score of 1 if the condition involved is immediately lifethreatening; 2 if it causes irreversible morbidity; 3 if it causes reversible morbidity requiring
immediate medical attention; and 4 if it causes reversible morbidity requiring medical attention.
Where there exists uncertainty in allocating a score, consideration is also given to the frequency at
which the condition occurs. For example, if a condition may reasonably be allocated a score of 2 or 3
but occurs commonly (>10%) it is scored as 2. If the condition occurrs infrequently (<10%) it would
receive a score of 3. The remaining columns of Table 2 are the author’s evaluation based on current
literature. For a summary of the strengths and limitations of each individual study included in this
evaluation, refer to Appendix 2.
12
Drug Class
Drug(s)
NRTIs
Abacavir
Tenofovir
All
NNRTIs
Protease
Inhibitors
Nevirapine
Genotype
Causal Association
Mechanism
Clinical Significance
Current Status
References
HLA-B*5701
Increased incidence of
abacavir hypersensitivity
reaction
Unknown but probably an enhanced
HLA-mediated immune response to
abacavir
Genetic testing to prevent use of
abacavir in those most susceptible to
abacavir hypersensitivity
Association supported by a strong body of observational data in racially
diverse populations, and one well-conducted randomized trial. Testing
recommended by US and UK guidelines since 2008
6, 8, 9, 11-14, 2328
HCP5 T335G
Alternative marker for HLAB*5701 screening
Linkage with HLA-B*5701 allele
Cheaper and easier testing procedure
than HLA-B*5701 testing
Association is as for HLA-B*5701. Assay requires further confirmation of
sensitivity and specificity
29, 30
MRP2
Increased incidence of
tenofovir-induced renal
tubulopathy
Undetermined but possibly
modulation of MRP2 function
leading to impaired tenofovir
elimination and subsequent toxicity
Genetic test to indicate those not
suitable for tenofovir therapy
Requires further verification of clinical relevance. Association supported by
limited observational data. Specific variant of the ABCC2 gene involved in
this association needs to be confirmed
44, 45
CFTR & SPINK-1
Increased incidence of
pancreatitis in the general
population
Pancreatitis is an adverse effect of
NRTIs thus CFTR and SPINK-1
mutations may further increase risk
Genetic test to isolate those more
susceptible to pancreatitis
Requires further verification of clinical relevance. Association only supported
by one case-control study and data from the general population. Evidence in
HIV patients includes a combined SPINK-1/CFTR endpoint
47-49, 51
Mitochondrial
haplogroups
Increased susceptibility to
NRTI-associated peripheral
neuropathy
Certain haplotypes may be more
susceptible to NRTI induced
mitochondrial depletion/dysfunction
Genetic test of mitochondrial
haplogroup to identify those at risk of
peripheral neuropathy with NRTI use
Requires further verification of clinical relevance. Association supported by
data generated from two case-control studies. No confirmation of
association with a particular haplogroup in different populations
58-60
HLACw8
HLA-DRB1*0101
Increased incidence of
hypersensitivity reaction
Unknown but probably an enhanced
HLA-mediated immune response to
nevirapine
Genetic testing to prevent use of
nevirapine in those susceptible to
nevirapine hypersensitivity
Requires further verification of clinical relevance. Each allele association
supported by limited observational data. HLA-DRB1*0101 association
complicated by involvement of CD4+ cell count
HLACw8 - 65, 67
HLA-DRB1*0101
- 66, 68
MRP1 C3435T
Decreased risk of
hepatotoxicity
Unknown but possibly altered MRP1
efflux of nevirapine in the gut
Genetic test may be able to predict
patients most (un)likely to develop
nevirapine associated hepatotoxicity
Requires further verification of clinical relevance. Association supported by
data from three case-control studies undertaken in various ethnicities
70, 73, 74
Efavirenz
CYP2B6 G516T
Increased plasma levels and
central nervous system
toxicity
Impaired hepatic metabolism of
efavirenz
Genetic test to guide appropriate
dosing
Strong association supported by a large volume of observational data
generated from populations of various ages and ethnicities. Other less
significant genetic markers require verification of clinical relevance to aid
creation of a pharmacogenetic algorithm
80, 85, 86, 88102, 104-107
Atazanavir
& Indinavir
UGT1A1*28
MRP1 variants
Increased risk of
hyperbilirubinemia
Impaired UGT1A1 bilirubin
conjugation exaggerates the dosedependent increase in bilirubin
caused by atazanavir and indinavir.
MRP1 mutation probably impairs
atazanavir elimination leading to
increased bilirubin
Unknown
UGT1A1*28 genetic test may identify
those most at risk of developing
hyperbilirubinemia, especially if
combined with MRP1 testing
Strong association (for UGT1A1*28) supported by numerous observational
studies in a range of ethnically diverse populations. Clinical acceptability of a
genetic test may be low because of the benign nature of hyperbilirubinemia
UGT1A1*28 +/MRP1 variants 110-114
All
ABCA1, APOA5,
APOC3, APOE
Increased likelihood of
protease inhibitor associated
hypertriglyceridemia
MRP1 C3435T 115
Genetic test incorporating relevant
risk alleles to form a genetic score may
predict those at risk of
hypertriglyceridemia
Strong association supported by a number of well-conducted observational
studies. Further verification of clinical relevance is made difficult by the
complexity of factors that affect lipid levels
Table 1. Summary of clinically important or potentially important, confirmed pharmacogenetic associations in HIV therapy
119, 121-125
13
Despite the success of introducing genetic testing for abacavir, some doubt remains regarding the
cost-effectiveness of routine HLA-B*5701 testing due to the inferior efficacy of abacavir-containing
regimens. Nevirapine hypersensitivity and NRTI-associated peripheral neuropathy are clinically
significant conditions however evidence supporting predictive pharmacogenetic testing for these and
all other candidate tests discussed is currently lacking. The associations between efavirenz plasma
levels and CYP2B6 G516T, and protease inhibitor-associated hypertriglyceridemia and unfavorable
ABCA1, APOA5, APOC3 and APOE genotypes are supported by large volumes of literature but exhibit
complexity that may limit their utility for pharmacogenetic testing. The connection between
atazanavir-/indinavir- associated hyperbilirubinemia and the UGT1A1*28 genotype is also well
supported by the literature however the clinical significance of hyperbilirubinemia is relatively low.
LEVELS OF EVIDENCE
CLINICAL SIGNIFICANCE
Recommendation
Supporting Evidence
A (recommended)
I - high level evidence including at least one randomized controlled
trial with clinical, laboratory or programmatic end-points
1 – Immediately life threatening
B (consider)
II- at least one high-quality study or several adequate studies with
clinical, laboratory or programmatic end-points
2 – Causes irreversible morbidity
C (optional)
III - observational cohort data, one or more case-controlled or
analytical studies adequately conducted
3 – Causes reversible morbidity requiring urgent
medical attention
IV - indicates expert opinion based on evaluation of other evidence
4 - Causes reversible morbidity requiring medical
attention
Table 3. Assessment of clinical relevance. Levels of evidence are based on the WHO 2006 assessment of evidence criteria.127 Clinical
significance evaluates the seriousness of the condition involved in the pharmacogenetic association.
Future of HIV Pharmacogenetics
Confirmed pharmacogenetic associations in HIV medicine have only been established for NRTIs,
NNRTIs and protease inhibitors. Numerous unconfirmed and insignificant associations for these
antiretroviral classes have been reported,15 and some early work has led to insignificant
pharmacogenetic findings for the new compounds, raltegravir128 and maraviroc.129 Future research is
likely to reveal numerous, as yet undiscovered pharmacogenetic associations for both old and new
antiretrovirals. This review has summarized the literature on HLA-B*5701 genetic testing to prevent
abacavir hypersensitivity and other promising pharmacogenetic associations in HIV therapy. An
assessment of the clinical utility of these associations revealed that, except in the case of abacavir,
their clinical relevance remains to be established. Notably, this evaluation also casts doubt over the
cost-effectiveness of HLA-B*5701 testing for abacavir. Some of the associations discussed appear too
complex for genetic testing in clinical practice. However evidence-based algorithms can
accommodate the multifactorial nature of drug responses. Such an approach has already been
attempted for antiretroviral-associated dyslipidemia119 and evidence suggests it may also be useful
for predicting efavirenz toxicity.89, 104-107
HIV pharmacogenetics must overcome various hurdles before genetic individualization of HAART
therapy becomes realistic. Many published studies in this field are underpowered and of low quality
(see appendix 2). Future work should evaluate associations most likely to be clinically relevant (see
box 2) in large, ethnically diverse populations.130, 131 Results should then be validated in independent
patient populations. Attention also needs to be given to ensuring studies are directed towards
14
Clinically Relevant
Cost
Effective
A Robust
Assay
Quick
Simple
Report
Sufficient
Education
Guideline
recom.
Comment
Level of
evidence
Clinical
Significance
Abacavir hypersensitivity
(HLA-B*5701)
AI
1
?
√
√
√
√
Successful introduction to clinical practice. Recent data indicating the
inferior efficacy of abacavir compared to other NRTIs places doubt over
the cost-effectiveness of HLA-B*5701 testing.
Abacavir hypersensitivity
(HCP5 T335G as a marker for HLAB*5701)
AI
1
?
?
X
X
X
May serve as a cheaper, easier alternative to HLA-B*5701 testing
pending further insight into assay specificity and sensitivity.
Tenofovir-induced renal
tubulopathy
(MRP2)
CIII
3
?
X
X
X
X
Insufficient evidence to confirm clinical relevance.
NRTI-associated pancreatitis
(CFTR & SPINK-1)
CIII
3
?
X
X
X
X
Insufficient evidence to confirm clinical relevance.
NRTI-associated peripheral
neuropathy
(Mitochondrial haplogroups)
CIII
2
?
X
X
X
X
Insufficient evidence to confirm clinical relevance.
Nevirapine hypersensitivity
(HLA-DRB1*0101 & HLA-Cω8)
CIII
1
?
X
X
X
X
Insufficient evidence to confirm clinical relevance. Hepatic reaction
association to HLA-DRB1*0101 allele complicated by association of
CD4+ cell count.
Nevirapine-associated hepatitis
(MRP1 C3435T)
CIII
3
?
X
X
X
X
Insufficient evidence to confirm clinical relevance.
Efavirenz and increase plasma
levels
(CYP2B6 G516T)
CII
3
?
X
X
X
X
Significant evidence to support association. An algorithm to account for
major sources of inter-individual variability may be useful.
Atazanavir- and indinavirassociated hyperbilirubinemia
(UGT1A1*28 & MRP1 variants)
CII
4
?
X
X
X
X
Strong association in the case of UGT1A1*28 however benign nature of
hyperbilirubinemia may limit clinical acceptability. Combined
UGT1A1*28/MRP1 genetic testing may be more predictive.
Protease inhibitor-associated
hypertriglyceridemia
(ABCA1, APOA5, APOC3, APOE)
CII
3
?
X
X
X
X
Significant supportive evidence of association. An algorithm may be
useful to account for complexity of genetic and non-genetic factors
involved in lipid regulation.
Table 2. Assessment of the clinical utility of pharmacogenetic associations in HIV therapy. Clinical relevance is assessed by the WHO 2006 levels of evidence criteria and clinical significance as outlined in Table 2.
The remaining columns are allocations made by the author based on current literature. √ = Yes/Available, ? = Uncertain/Unknown, X = No/Not available.
15
acquiring guideline recommendation by generating clinically relevant information such as diagnostic
test criteria (eg. sensitivity and specificity) and cost-effectiveness figures. With high quality, clinically
applicable data, influential groups such as regulatory agencies and the pharmaceutical industry are
far more likely to become involved in educating, encouraging and enforcing the use of a
pharmacogenetic test.131, 132 It must also be demonstrated that the pharmacogenetic test does
actually improve clinical outcome outside the controlled settings of a randomized trial. Positive
follow-up data on the incidence of abacavir hypersensitivity reactions since the introduction of
guideline recommendations for HLA-B*5701 testing will almost certainly increase physician
compliance with this recommendation and is also likely to improve the acceptance of
pharmacogenetic testing in HIV medicine.
DRUG CHARACTERISTICS
Narrow therapeutic index
Difficulty predicting response or adverse event
Large interindividual variability in response
Box 2. Characteristics of drugs
most likely to benefit from a
pharmacogenetic test.
Adapted from Swen et al
(2007)131
Consistent pharmacokinetic-pharmacodynamic relationship
Long-term treatment
The future of HIV pharmacogenetics extends beyond the prospective identification of those
susceptible to a specific antiretroviral drug response. Kaslow et al (2001)133 reported that the HLAB*27 and B*57 alleles were associated with a favorable immune response to an experimental HIV
vaccine. Cressy & Lallemant (2010)134 attempted to identify genetic factors that lead to prolonged
nevirapine exposure and hence rapid selection of resistant virus in women given the antiretroviral for
prevention of mother-to-child HIV transmission. Genetic testing could also become useful for
identifying patients most likely to succeed on HAART or more importantly, a particular HAART
regimen. 85, 110, 135-148
The current shift from isolated analyses of specific genetic variants to genome wide association
studies should enhance our understanding of the complex genetic mechanisms underlying variability
in drug response. Furthermore, numerous new potential targets for pharmacogenetic research may
be revealed. More affordable methods of individual patient testing will also be important,
particularly for HIV pharmacogenetics. While cost-effectiveness of a pharmacogenetic test is
important for its implementation into healthcare systems of the developed world, it is absolutely
essential if such methods are ever to become accessible to the developing world where the demand
for antiretroviral therapy is greatest.
16
Appendix 1 – Keyword Search
Databases searched: PubMed and Embase
Last search: 8 August 2010
Search variables:
#1 'HIV' OR 'human immunodeficiency virus' OR 'AIDS' OR 'acquired immunodeficiency syndrome'
#2 'ARV' OR 'antiretroviral' OR 'HAART' OR 'highly active antiretroviral therapy' OR 'ART' OR
'antiretroviral therapy' OR 'NRTI' OR 'nucleoside reverse transcriptase inhibitor' OR 'nucleotide
reverse transcriptase inhibitor' 'NNRTI' OR 'non-nucleoside reverse transcriptase inhibitor' OR 'PI' OR
'protease inhibitor' OR 'fusion inhibitor' OR 'integrase inhibitor' OR 'CCR5' OR 'cellular coreceptor 5'
OR 'lamivudine' OR 'abacavir' OR 'azidothymidine' OR 'AZT' OR 'stavudine' OR 'didanosine' OR
'tenofovir' OR 'emtricitabine' OR 'efavirenz' OR 'nevirapine' OR 'lopinavir' OR 'atazanavir' OR
'indinavir' OR 'nelfinavir' OR 'ritinovir' OR 'saquinavir'
#3 'pharmacogenetic' OR 'pharmacogenomic' OR 'genetic' OR 'genetic testing' OR 'HLA-B*5701'
#1 and #2 and #3
Appendix 2 – Individual study evaluation
Studies describing the associations discussed above were assessed for methodological quality.
Studies were evaluated based on the US Preventive Services Task Force Quality Rating Criteria for
randomized controlled trials (RCTs), cohort studies, and case control studies.149 Cross sectional
studies were evaluated with the criteria for cohort studies without consideration of follow-up. The
single non-randomized trial was evaluated with the criteria for RCTs without consideration of
randomization. Case reports were not evaluated but are mentioned in the table. The criteria are
briefly described:
RCTs and cohort studies
 Adequate randomization (RCT), or consideration of confounders (cohort)
 Maintenance of comparable groups
 No important differential loss to follow-up or high rate of loss to follow-up
 Equal, reliable and valid measurements
 Clearly defined intervention
 Important outcome/s considered
 Intention to treat analysis (RCT), or adequate adjustment for potential confounders (cohort)
Good – Meets all criteria. Comparable groups assembled initially and maintained throughout the
study (follow-up ≥80%); reliable and valid measurement instruments used and applied equally to
both groups; interventions are clearly indicated; important outcomes considered; and appropriate
attention to confounders in analysis.
Fair – Meets most of the criteria without any of the important limitations mentioned in the “poor”
category. Generally comparable groups initially assembled but some question remains regarding
17
differences that occurred in follow-up; measurement instruments acceptable (although not ideal)
and generally applied equally; some but not all important outcomes considered; and some but not all
potential confounders are accounted for.
Poor – If any of the following limitations are present: Groups assembled initially are not comparable
or maintained throughout the study; unreliable or invalid measurement instruments used or not
applied equally among groups (including not masking outcome assessment); or key confounders are
given little attention.
Case control studies
 Accurate ascertainment of cases
 Non-biased selection of cases and controls
 Adequate response rate
 Diagnostic testing procedure applied equally to each group
 Accurate measure of exposure applied equally to each group
 Appropriate attention given to potential confounders
Good – Appropriate ascertainment of cases and non-biased selection of cases and controls; exclusion
criteria applied equally to cases and controls; response rate equal to or greater than 80%; diagnostic
procedures and measurements are accurate and applied equally to cases and controls; and
appropriate attention to confounders.
Fair – Recent, relevant, without major apparent selection or diagnostic work-up bias but with
response rate less than 80% or attention to some but not all important confounders.
Poor – Major selection or diagnostic work-up biases; response rate <50%; or inattention to
confounders.
18
Study Characteristics
Drug Class
NRTIs
Drug(s)
Abacavir
Genotype
Comments on Methodology
Grading
Ref
Fair
8
Well defined outcome. Potential for unblinding of HLA
status. Single physician deciding outcome.
Good
9
Well defined outcome. Potential for unblinding of HLA
status.
Good
11
Immunologically confirmed HSR
Separate analysis of Blacks and Whites. Immunologically
confirmed outcome. Very low number of confirmed
outcomes in Black patients (n=5)
Good
12
1956 abacavir naive patients
from 19 countries
Immunologically confirmed HSR
Large study population. Immunologically confirmed
outcome and clinically diagnosed outcome. No multi-ethnic
analyses owing to large white dominance in study group.
Good
13
Case control & Cohort
49 French patients previously
exposed to abacavir (case
control) & 137 French
patients due to begin
abacavir (cohort)
Criteria defined HSR
Unspecified diagnostic criteria that appears to exaggerate
HSR incidence. Limited consideration of confounders. Time
separated and small control group.
Poor
14
Martin et al (2004)
Case control
200 patients from Mallal et al
(2002) and an extra 48
patients from the same clinic
Immunologically confirmed HSR
Consideration of Hsp70-Hom variant. White patients only.
Good
23
Phillips et al (2005)
Case control
7 patch test positive patients
and 11 abacavir tolerant
controls
Patch test response
Repeat testing to confirm outcome. HLA-B*5701 status not
the primary determinant. Small sample size.
Fair
24
Colombo et al (2008)
Cross sectional
1103 participants in the Swiss
HIV Cohort Study
HCP5 T335G status
Well defined HSR status. Evaluation of discordant patients.
Large study population. Potential for unblinding of HLA
status.
Good
29
Rodriguez-Novoa et al
(2010)
Cross sectional
245 abacavir naive patients
HCP5 T335G status
Evaluation of discordant patient. Loosely defined HSR
status.
Fair
30
Author (year)
Design
Population
Primary Outcome
Hetherington et al (2002)
Case control
85 patients, 115 controls
from the GSK database of
clinical trials for abacavir
Clinically diagnosed HSR
Mallal et al (2002)
Nested cohort
First 200 patients exposed to
abacavir in the Western
Australia HIV Cohort Study
Criteria defined HSR
Rauch et al (2006)
Case control
131 cases, 140 controls from
the Swiss HIV Cohort study
Criteria defined HSR
Saag et al (2008)
Case control
130 white cases, 202 white
controls. 69 black cases, 206
black controls
Mallal et al (2008)
RCT
Zucman et al (2007)
HLA-B*5701
HCP5 T335G
Confounders well adjusted for. Imperfect matching
between cases and controls. Limited analysis of confirmed
HSR.
19
Tenofovir
All
MRP2
CFTR & SPINK1
Izzedine et al (2006)
Case control
13 case patients, 17 tenofovir
treated controls
Tenofovir-induced renal
tubulopathy
Rodriguez-Novoa et al
(2009)
Case control
115 consecutive patients
presenting at a single clinic
Kidney tubular dysfunction
Felley et al (2004)
Case control
51 patients with
hyperamylasemia, 51
matched controls
Hulgan et al (2005)
Case control
Canter et al (2008)
Fair
44
Well defined outcome. Large number of confounders
considered. Small number of cases (n=19).
Good
45
Hyperamylasemia
Pancreatitis not the primary outcome. Consideration of a
large number of confounders. Low number of pancreatitis
cases (n=10).
Poor
51
147 patients with any grade
of peripheral neuropathy, 362
control patients without
peripheral neuropathy
Peripheral neuropathy of any
grade
Long follow-up of cases and controls (3 yrs). No
consideration of potentially important confounders such as
smoking or diabetes. Exclusion of patients with prior
peripheral neuropathy.
Fair
58
Case control
70 patients with any grade of
peripheral neuropathy, 180
control patients without
peripheral neuropathy
Peripheral neuropathy of any
grade
No consideration of potentially important confounders
such as smoking or diabetes. Exclusion of patients with
prior peripheral neuropathy. White study participants only.
Fair
59
Canter et al (2010)
Case control
51 non-Hispanic black
patients from the AIDS
Clinical Trials
Group study 384 who had
developed peripheral
neuropathy, 105 controls
from the same trial
Peripheral neuropathy of any
grade
No consideration of potentially important confounders
such as smoking or diabetes. Black study participants only.
Fair
60
Gatanaga et al (2007)
Case control
11 case patients, 29
nevirapine using controls
Nevirapine HSR
Small study population. Imprecise definition of primary
outcome. Patients only of Japanese ethnicity.
Fair
65
Littera et al (2006)
Case control
13 nevirapine hypersensitive
case patients, 36 tolerant
controls
Nevirapine HSR
Small study population. Patients only of Sardinian ethnicity.
Exclusion of patients with skin rash or late side effects
(>6wks). Confounding variables well accounted for.
Good
67
Martin et al (2005)
Case control
26 cases of nevirapine HSR
from the Western Australia
HIV cohort, 209 controls from
same study
Nevirapine HSR
Determinant was interaction between HLA-DRB1*0101 and
CD4+ count. Well defined outcome but not verified by
another physician and potential for unblinding of HLA
status.
Fair
66
Vitezica et al (2008)
Cohort
21 patients receiving
efavirenz or nevirapine from a
French cohort
Cutaneous drug reaction
Combined exposure (efavirenz or nevirapine). Poorly
defined outcome. Small number of cases (n=6).
Poor
68
Haas et al (2006)
Case Control
53 cases and 108 matched
controls from the Gilead
study protocol FTC-302
Grade 3 or 4 hepatotoxicity
Well defined exposure and outcome. Small number of nonblack races included in analysis.
Good
70
Mitochondrial
haplogroups
NNRTIs
Nevirapine
HLACw8
HLADRB1*0101
Small study population. Prior renal function not considered
in analyses.
MRP1 C3435T
20
Efavirenz
Ritchie et al (2006)
Case control
20 case patients using their
first NNRTI and 49 matched
controls from the
Comprehensive Care Center
in Nashville, Tennessee.
Ciccacci et al (2010) abstract only
Case control
78 cases and 78 controls from
Mozambique
Nevirapine-induced hepatotoxicity
Hasse et al (2005)
Case report
33yo Thai, female patient
using efavirenz
Severe psychosis
Haas et al (2005)
Cohort
504 patients participating in
the Adult AIDS Clinical Trials
Group study 384 genetic
analysis
Long-term response to treatment
Ribaudo et al (2006)
Cross sectional
152 evaluable subjects from
the AIDS Clinical Trials Group
(ACTG) study
Efavirenz pharmacokinetics
Saitoh et al (2007)
Cohort
71 child patients in Pediatric
AIDS Clinical Trials Group 382
(PACTG 382),
Efavirenz pharmacokinetics and
resistance
Selection criteria removes children that may have switched
from efavirenz prior to 6mths of therapy. Ethnicities
combined in analysis.
Motsinger et al (2006)
Cohort
304 ACTG 384 participants
randomized to receive
efavirenz
Efavirenz pharmacokinetics and
response to treatment
Separation of data from different races. Efavirenz plasma
levels analyzed as a dichotomous outcome.
Good
89
Rodriguez-Novoa et al
(2005)
Cohort
100 consecutive patients
initiating efavirenz at a clinic
in Madrid
Efavirenz plasma concentration
White only participants. Exclusion criteria not appropriate
(eg. removed those with poor compliance who may be
more likely to exhibit high plasma levels). Most
confounders removed by exclusion criteria.
Fair
90
Tsuchiya et al (2004)
Cross sectional
35 patients on efavirenz being
treated at the AIDS clinical
entre, IMCJ
Efavirenz plasma concentration
Japanese only patients. Exclusion criteria not appropriate
(eg. removed those with poor compliance who may be
more likely to exhibit high plasma levels). Most
confounders removed by exclusion criteria.
Fair
91
Hepatotoxicity
Uncertainty regarding the sourcing of controls. Exposure
included nevirapine and efavirenz in analysis. Lose
definition of hepatotoxicity.
Poor
73
Many uncertainties in methodology owing to limited
information available in abstract. In particular with regard
to participant selection and outcome measure.
Not
possible
74
N/A
N/A
80
Increased plasma level or CNS symptoms not the primary
outcome. Long follow up. Thorough analysis of different
races present in study population. Could have included
more confounders in analysis (eg. Concomitant
medications, smoking status)
Fair
85
Good
86
Fair
88
CYP2B6 G516T
Model applied to predict likely plasma concentrations
rather than actual clinical measurements
21
Cross sectional
163 patients recruited
prospectively in a previous
study and 6 additional
individuals characterized by
very high plasma efavirenz
levels identified through
routine TDM
Efavirenz plasma concentration
CYP2B6 G516T grouped with other loss of function alleles.
Limited consideration of confounders.
Poor
92
Cohort
202 patients randomized to
receive efavirenz in study
A5097s from the Adult AIDS
Clinical Trials Group
Questionnaire identified CNS side
effects
Well defined exposure and outcome. Questionable clinical
relevance of using a questionnaire.
Good
93
Chen et al (2010)
Cross sectional
159 patients receiving
antiretroviral therapy (70
receiving efavirenz) at
Shanghai Public Health
Clinical Center
Efavirenz plasma concentration
No consideration for confounding variables.
Poor
94
Gupta et al (2008)
Cross sectional
13 hemodialysis patients
receiving efavirenz
Efavirenz pharmacokinetics
CYP2B6 516G>T status not the focus of this study. No
consideration of confounders. Very small study population
(n=11 with genotypic data available using efavirenz)
Poor
95
Leger et al (2009)
Cohort
45 Haitian patients receiving
efavirenz
Efavirenz pharmacokinetics
Confounding adjusted for. Results validated in a separate
group of African American patients.
Good
96
Nyakutira et al (2008)
Cross sectional
74 outpatients from clinics in
Harare receiving efavirenz
Efavirenz pharmacokinetics
Sex the only confounder considered.
Fair
97
Ramachandran et al (2009)
Cross sectional
15 patients receiving
efavirenz from an outpatient
clinic in India
Efavirenz pharmacokinetics
No confounder accounted for. No validation of plasma
concentrations. Very small study size. Patients may have
been on therapy for a min of 1 week.
Poor
98
Lowenhaupt et al (2007)
Case report
12yo white female
Psychosis
N/A
N/A
99
Rotger et al (2005)
Cross sectional
(pharmacokinetic
study)/Cohort (CNS
toxicity study)
167 patients receiving
efavirenz in the Swiss HIV
Cohort Study
Efavirenz pharmacokinetics and
CNS toxicity
Questionable clinical significance of reporting CNS
symptoms by questionnaire. No evaluation of confounders
in PK side of study. Not stated when assessment of CNS
toxicity performed.
Poor
100
Rotger et al (2007)
Haas et al (2004)
22
Protease
Inhibitors
Atazanavir
& Indinavir
Ribaudo et al (2010)
Cross sectional
(pharmacokinetic)/Cohort
(treatment response)
Patients from the AIDS
Clinical Trials Group. 317
pharmacokinetics study and
643
for treatment response
Efavirenz pharmacokinetics and
treatment response
Thorough evaluation of confounders. Assessment of CNS
toxicity truncated at 24 weeks.
Good
101
Gatanaga et al (2007)
Non-randomized trial
456 patients receiving or due
to receive efavirenz at
hospitals in Japan
Efavirenz plasma concentration
after dose adjustment (if required)
Follow up appeared sufficient. Clear definition of criteria
for dose change.
Good
102
di Iulio et al (2009)
Cross sectional
169 patients previously
characterized for their
CYP2B6 genotype
Efavirenz plasma concentration
and its primary metabolites
Primary determinant was CYP2A6 status. Confounding well
accounted for.
Fair
104
Fair
105
Kwara et al (2009)
Cohort
94 Ghanaian patients
Efavirenz plasma concentration
Significant percentage (60%) of participants had
tuberculosis. Primary determinant included CYP2A6 and
UGT2B7 status. Confounding well accounted for. Blood
sampling not performed at consistent time points (4 and
8wks for 66 pts, 2wks for 28 pts).
Kwara et al (2009)
Cohort
74 patients enrolled in a pilot
trial of a new antiretroviral
regimen undertaken in Ghana
Efavirenz plasma concentration
Significant percentage (46%) of participants had
tuberculosis. Primary determinant included CYP2A6 status.
Confounding well accounted for.
Fair
106
Arab-Alameddine et al
(2009)
Cohort
169 patients from the Swiss
HIV Cohort Study
Efavirenz pharmacokinetics
CYP2B6 status evaluated along with CYP2A6 and CYP3A4/5.
Confounders well accounted for.
Good
107
Anderson et al (2006)
Cohort
33 antiretroviral-naive
patients who participated in a
randomized pharmacological
study of indinavir, lamivudine,
and zidovudine.
Antiretroviral pharmacokinetics
Limited assessment of confounders (sex, weight, race).
Number of patients from non-white races too low for
accurate stratified analysis. Multiple genes analyzed
(CYP3A5, MRP1, MRP2, MRP4, BCRP, UGT1A1).
Fair
110
Boyd et al (2006)
Cohort
96 Thai patients receiving
indinavir
Hyperbilirubinemia
Clinically relevant outcome but not compared with plasma
levels in this study. Confounding not considered. Outcome
poorly defined (total bilirubin >1 mg/dl).
Poor
111
Cohort
129 Korean patients initiating
atazanavir at Seoul National
University Hospital
hyperbilirubinemia
MRP1 influence also considered. Exclusion of patients with
poor virological response may have excluded those with
adverse effects to treatment. Atazanavir concentration not
measured. 6 patients that developed jaundice not included
in analyses.
Poor
112
UGT1A1*28
+/- MRP1
Park et al (2010)
23
Patients with poor adherence excluded introducing a
possible selection bias. Thorough analysis of possible
confounders. Atazanavir plasma levels compared against
bilirubin levels.
Poor
113
Hyperbilirubinemia
Long follow-up. Thorough analysis of possible confounders.
Clinically relevant outcome (jaundice). Atazanavir and
indinavir users combined in analysis. Outcome compared
between PI users with UGT1A1 *28and non-PI users
without UGT1A1 *28. More relevant to compare PI users
with UGT1A1 *28 to PI users without UGT1A1 *28.
Good
114
Cohort
74 antiretroviral-experienced
patients initiating atazanavir
with 2 NRTIs at a clinic in
Madrid
Plasma atazanavir and bilirubin
concentrations
Patients with poor adherence excluded introducing a
possible selection bias. Lack of explanation as to why
plasma levels only measurable in 57 patients. Confounders
well accounted for. Atazanavir and bilirubin levels
measured.
Poor
115
Arnedo et al (2007)
Cohort
419 antiretroviral treated
participants of the Swiss HIV
Cohort study
Dyslipidemia
Thorough consideration of confounders. Well defined
outcome. Scoring system needs validation in an
independent population.
Good
119
Tarr et al (2005)
Cohort
329 antiretroviral treated
patients enrolled in the Swiss
HIV Cohort study
Triglyceride, HDL and Non-HDL
concentrations, and lipoatrophy
Confounding well accounted for. Low drop-out rate. LDL is
a more commonly used lipid marker than non-HDL.
Good
121
Fauvel et al (2001)
Cross sectional
60 consecutive male patients
using at least one PI attending
an HIV follow-up consultation
Lipids, apolipoproteins, lipoparticle
levels were determined, together
with glucose and markers of insulin
secretion.
Exclusion criteria selected patients less likely to exhibit
dyslipidemia which may not be evenly distributed across
genotypes tested. Limited consideration of confounders.
Only men included in study. Cross sectional design not well
suited to outcome.
Poor
122
Foulkes et al (2006)
Cross sectional
440 patients enrolled in
selected AIDS Clinical Trial
Group studies on stable PI
therapy
Plasma lipids
Cross sectional design not well suited to outcome. Analyses
stratified by race. Consideration of numerous possible
confounders.
Fair
123
Bonnet et al (2008)
Cross sectional
40 white, male patients
attending a follow-up
consultation at University
Hospital in Southern France
Plasma lipids and lipoatrophy
Cross sectional design not well suited to outcome. Limited
consideration of confounders in final analysis.
Poor
124
Rotger et al (2009)
Cohort
745 patients from the Swiss
HIV Cohort study
Total cholesterol, HDL cholesterol,
and triglycerides
Confounders thoroughly accounted for. Long duration.
Grouped antiretrovirals by potential to cause dyslipidemia
which allows for comparison between drug classes, drug
regimens and particular drugs.
Good
125
Rodriguez-Novoa et al
(2007)
Cohort
118 patients initiating
atazanavir at a single institute
Cohort
96 patients from the genetics
project of the Swiss HIV
Cohort Study receiving
atazanavir or indinavir
Rodriguez-Novoa et al
(2006)
Rotger et al (2005)
Atazanavir plasma levels and
hyperbilirubinemia
MRP1 C3435T
All
ABCA1,
APOA5,
APOC3, APOE
24
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