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WorksheetsHIV PGx - Stev
Total questions: 34
Worksheet time: 18mins
ART (antiretroviral therapy) is highly effective that HIV has evolved into a chronic disease. However ART is complicated by:
Development of resistance to ART
Complex drug distribution, transport and metabolism
Drug associated toxicities
All of the above
The Role of PGx has expanded greatly over past 10-20 years, but not yet commonly used for:
–CYP450 enzymes
–UGT (5-diphospho-glucuronosyltransferase)
What are some example where PGx are use in HIV?
HIV resistance testing started in the early 2000’s
HLA testing to predict hypersensitivity reaction to abacavir
Tropism testing before using maraviroc
All of the above
PGx for virus characteristics consist of:
–Resistance testing
–Coreceptor tropism
True
False
•PGx for host (patient) characteristics in HIV Tx are:
UGT (5´-diphosph-glucuronosyltransferase)
CYP2B6
HLA-B*5701
All of the above
Drug Resistance mutations occur frequently and spontaneously due to lack of 3´ to 5´ proofreading mechanism during viral replication
True
False
Drug Resistance mutations occur by amino acid substitutions, deletions and additions to the HIV genes for:
Protease
Envelope genes
Integrase
Reverse transcriptase
All of the above
In Drug Resistance Testing, the HIV with no mutations is referred to wild-type virus, what are other considerations to keep in mind about ART,HIV and Resistance?
Resistance mutations slows the speed at which the mutated virus can replicate
If resistance exists and the ART is removed, wild-type virus will become predominant again
The resistant HIV is archived
–And will become predominant again if ART is restarted with the drug that the HIV is resistant to
All of the above
HIV resistance testing has been recommended since 2000 and Current DHHS guidelines recommend testing at:
Before starting ART if not started soon after diagnosis
Resistance suspected due to increasing HIV RNA viral load for patients on ART or if viral load does decrease as expected
Initial diagnosis:
• May have been infected with resistant virus
• 6-16% of patients may have transmitted resistance to at least one medication
All of the above
which of the following are characteristics of current Genotype testing for Drug Resistance?
Preferred method according to guidelines
All sequence the protease and transcriptase genes
Tests for integrase and envelope genes also available and must be requested separately
Guidelines recommend consulting with an expert for interpretation
All of the above
•Phenotypic testing in drug resitance testing:
–Inserts the HIV virus genes into a pseudovirus
–Pseudovirus replicated invitro with various concentrations of drugs to find IC50
–More expensive and takes longer for results (2-3 weeks)
–When compared to genotypic testing, results are comparable
–Can be useful when patient has multi-drug resistant virus
True
False
Practical considerations during Drug Resistance Testing are the following:
Must be conducted while patient is still on failed ART or within 4 weeks of stopping
Interpretation of resistance testing must include all testing ever conducted
Must consider patient compliance at time of testing
Viral load ideally must be ≥ 1000 copies/mL
OR at least ≥ 500 copies/mL at time of testing
All of the above
Proviral DNA Resistance Testing is:
- Designed to analyze HIV-1 proviral DNA located in host cells
- Detect drug resistance mutations within proviral HIV DNA archived within peripheral blood mononuclear cells of the patient
True
False
What do the guidelines say about Proviral DNA Resistance Testing?
The clinical utility of proviral DNA resistance testing has yet to be fully determined
–May be useful when switching a patient's ART regimen when:
•HIV viral load is nondetectable and there are no prior resistance results available
•Or if there is low-level viremia and a plasma HIV RNA genotypic assay is unlikely to be successful
None of the above
All of the above
Coreceptor Tropism:
As time passes and HIV virus mutates:
–Virus becomes X4-tropic or dual-tropic
Early during infection
– R5-tropic virus is common
Virus can bind to:
–CCR5 exclusively (R5-tropic)
–CXCR4 exclusively (X4-tropic)
–Both CCR5 and CXCR4 (dual- or mixed- tropic)
HIV entry into cell
1.Virus attaches to CD4 receptor
2.Virus binds to coreceptor CCR5 or CXCR4
3.Fusion of the viral and cell membranes
Maraviroc is the only coreceptor antagonist:
–Blocks binding to CCR5 coreceptor
–Only effective against R5-tropic HIV
•Not effective against X4-tropic or dual tropic
True
False
Coreceptor Trospism - Phenotypic testing
–Pseudoviruses are prepared using the patient’s virus envelope gene
–Pseudoviruses infect target cells expressing either CCR5 or CXCR4
–Results
•If only CCR5 cells are infected, then R5-tropic
•If only CXCR4 cells are infected, the X4-tropic
•If infect both, then dual-tropic
True
False
Coreceptor Tropism - Genotypic testing:
Some retrospective studies have been conducted to compare it to phenotypic testing with favorable results
No prospective studies have been conducted with this method
An algorithm is used to predict the HIV coreceptor tropism
Patient’s HIV envelope genes are sequenced
Assays that sequence the V3-coding sequence of the HIV envelope gene recently became available
Current guideline recommendations on Coreceptor Tropism:
All of the above
Phenotypic testing for tropism should be conducted before using maraviroc or if tx with maraviroc is failing
Phenotypic is recommended over genotypic testing because there are no prospective studies using genotypic testing
Genotypic testing
•Is considered an alternate, faster and cheaper
•Can also be used if viral load is < 1,000 copies/mL
HSR to Abacavir is due to HLA-B*5701 and:
Occurs within 6 weeks of starting tx
Can develop rapidly and become life threatening
Will worsen if abacavir continued
Median time to occurrence is 9 days
All of the above
Carriers of HLA-B*5701 can develop HSR to abacavir tx.
–It is diagnoses by occurrence of 2 or more of the following symptoms
•Fever
•Rash (not always present)
•GI symptoms
•Constitutional symptoms (night sweats, myalgias, fatigue, anorexia (sometimes with nausea and vomiting), or weight loss).
•Respiratory symptoms
–Fever, rash and general malaise reported by more than 50% of patients
True
False
HLA-B*5701 carrier taking Abacavir can have a HSR, and it is difficult to diagnose due to non-specific symptoms and easy to misdiagnose. If HSR likely or cannot be ruled out:
–Abacavir should be stopped
–Should not be restarted
True
False
HSR due to HLA-B*5701 while taking Abacavir encloses the following characteristics:
first evidence in 2022 that this HSR was linked to HLA
Studies indicated that the presence of HLA-B*5701 predicted the HSR
Frequency of HLA-B*5701 is variable
–Southwest Asia: 3.8%-19.6%
–European: 1.4%-10.2%
–African: 0%-3.2%
All of the above
•FDA has NOT added a boxed warning to abacavir and all abacavir containing products for patients positive for HLA-B*5701
True
False
HLA-B*5701 Guidelines state that:
All patients (regardless of ancestry) should be tested for HLA-B*5701 before tx with abacavir and if HLA-B*5701 positive:
Avoid abacavir tx
Abacavir allergy should be noted in patients' medical record
Educate patient on importance of this test result
Only need to test once in lifetime
All of the above
CYP2B6 allele variants concerns while in HIV Tx include:
Lab results reported as:
–(*) alleles
–C.516G>T
CYP2B6
-Major component of nevirapine metabolism
-Accounts for 90% of efavirenz metabolism
All of the above
Both have large variations in kinetics
–Large portion can be explained by genetic factors
Affects efavirenz and nevirapine (NNRTIs)
Nevirapine and CYP2B6 interaction exist, however which of the following are concerns about Nevirapine Tx:
Despite PGx, screening is not used for nevirapine dosing
T/T substitutions at the 516 position
In adults: increases 12 hour post dose concentrations 1.5-1.7x
In children: clearance reduced by 30%
All of the above
Efavirenz
–Narrow therapeutic range
–CYP2B6 516 G/T or T/T: poor or slow metabolizers which leads to higher concentrations
–Occurs in up to 20% of African ancestry
True
False
Efavirenz
–Longer half-life: increases chance of resistance
–20-40% of patients experience CNS side effects when receiving the standard 600mg daily dose
•3x more frequent at higher efavirenz concentrations
True
False
UGT :5´-diphosph-glucuronosyltransferase
•Carry out glucuronidation reactions allowing compounds (bilirubin) to be eliminated in bile or urine
•UGT1A1 involved in glucuronidation of bilirubin
–Variation in its genes leads to 2 syndromes
•Crigler-Najjar syndrome
–Rare, absence of UGT1A1 activity, patients die in childhood if not treated
•Gilbert syndrome
True
False
•Gilbert syndrome - UGT VARIATION
–Most common
–Affects ~10% of the population
–Causes mild unconjugated hyperbilirubinemia
–Wildtype allele designated as UGT1A1*1
–Variant allele designated as UGT1A1*28
•Most common variant found in Gilbert Syndrome
•Decreased enzyme activity from this decreases bilirubin clearance by 40%
•Frequency of UGT*1A1*28
–African heritage: 43%
–European: 36-39%
–Asian: 11-19%
True
False
UGT & PIs
•Several protease inhibitors inhibit UGT1A1
•Atazanavir/ritonavir in patients with Gilbert syndrome
–Bilirubin levels often exceed 5X the upper limit of normal
–Leads to higher stop rates due to jaundice and/or scleral icterus
True
False
UGT & PI
•DHHS Guidelines for use of ART in adults
–No recommendations at this time to test for UGT1A1*28
•Lack of studies
•Cost effectiveness is uncertain
True
False
UGT & PI
CPIC (Clinical Pharmacogenetics Implementation Consortium) for UGT1A1 and atazanavir
–Normal metabolizer – no dose adjustment
–Intermediate metabolizers – no dose adjustment
–Poor metabolizer – Consider alternate medication
True
False
•Currently there are 3 genetics tests regularly used in the treatment of HIV:
–Resistance testing
–HLA-B*5701
–Tropism for CCR5/CXCR4
•Others not in common use:
–CYP2B6
–UGT
True
False
