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Infectious Disease EXAM 4 - HIV
Infectious Disease EXAM 4 - HIV
34
Pharmacology
Graduate
02/12/2011

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Term
HIV is a retrovirus subset lentivirus, which means that there is an interval between the initial infection and the onset of symptoms
HIV infects the CD4 T cells and begins to replicate rapidly
gradual deterioration of immune function and eventual destruction of lymphoid and immunologic organs is central to triggering the immunosuppression that leads to AIDS
healthy adults have ~ 1000 CD4
AIDS CD4 < 200
reverse transcriptase copies HIV genome into the DNA of the host cell, genetic material is permanently incorporated into the infected cell genome
Definition
HIV replication
Term
sexual
perinatal
blood: parenteral, occupational exposures, blood products
increased risk: viral load of source, frequency of exposure
rarely: other body fluids, organ transplant
NOT BY: inanimate objects, insect vector, casual contact
Definition
routes of HIV transmission
Term
Acute HIV infection:
Day 0 = primary infection
Week 4 = acute retroviral syndrome (flu-like symptoms)

Asymptomatic HIV infection:
Week 6 - 6 Months = detectable antibodies, immunologic control (decrease in CD4 cells), plasma viral load stabilizes, clinical latency

Symptomatic HIV Infection:
Year 5-9 = constitutional illness, virologic progression, immunosuppression

AIDS:
Year 10-12 years = AIDS defining illness
Year 11.5-12 = death
Definition
course of HIV infection without antiretroviral therapy
Term
HIV +
AND
CD4 < 200
OR
Defining Illness: opportunistic infections (bacterial, mycobacterial, parasitic, fungal, viral); cancers (kaposi sarcoma, lymphoma, cervical); HIV illness (encephalopathy, myopathy, nephropathy, wasting)
Definition
clinical definition of AIDS
Term
Antibody tests: rapid HIV test kit, ELISA, western blot
antibody window: repeat testing should be done at 6 week, 6 months, and 1 year b/c it could take up to one year for antibodies to be produced
antigen test: HIV DNA PCR, HIV RNA viral load
CD4 count
Definition
*diagnostic testing for HIV*
Term
whenever the index of suspicion is high: focus on risk activities not risk groups
AIDS defining illness
unexplained immunosuppression
suspicious illnesses: mucocutaneous candidiasis, cervical hyperplasia, acute retroviral syndrome, current or prior STD
Definition
who should get tested for HIV?
Term
genotype: tests viral genes for mutations of drug resistance, takes 1-2 weeks
phenotype: tests virus ability to replicate in presence of meds, takes 2-3 weeks, harder to interpret, more expensive

recommended for:
acute HIV infection
chronic HIV infection
virologic failure
pregnant patients
Definition
HIV resistance testing: difference between genotype and phenotype testing and who they are recommended for
Term
AIDS defining illness
HIV associated nephropathy
pregnancy
coinfection with HBV and HBV is being treated
if asymptomatic, based on CD4 counts and viral titers, risks and benefits of therapy, and patient willingness to begin treatment

CD4 Count <350 and Plasma HIV RNA levels < 100,000
Treat

CD4 Count <350 and Plasma HIV RNA level >100,000
Treat

CD4 count = 350-500 and Plasma HIV RNA level <100,000
Treatment recommended and should be offered following full discussion of pros and cons with each patient.

CD4 Count = 350-500 and HIV RNA level >100,000
Treatment should be recommended and should be offered following full discussion of pros and cons with each patient

CD4 Count > 500 and HIV RNA level <100,000
Typically defer treatment, but treatment is optional

CD4 Count >500 and HIV RNA level >100,000
treatment optional
Definition
indications for HIV treatment
Term
risks:
drug ADRs so decreased QOL
risk of drug resistance
limitation of future drug options

benefits:
control easier to achieve and maintain
delay immunocompromise
lower risk of resistance
reduction of HIV transmission?
Definition
risks and benefits of early HIV therapy
Term
risks:
risk of irreversible immunocompromise
increased difficulty in suppressing viral replication
increased risk of HIV transmission

benefits:
avoid ADRs so better QOL
delays drug resistance
preserves future drug options
Definition
risks and benefits of delayed HIV therapy
Term
barriers to adherence:
incomplete understanding
side effects
poor communication
concealing disease
drug abuse
poor social situations
unable to travel, make office visits
psychiatric illness
other medical problems

strategies for improving adherence:
assessed and reinforced at every visit
negotiate a treatment plan patient will commit to
find daily triggers to taking medications
simplify food requirements
simplified regimens (BID dosing, lower pill burden)
clearly written instructions, including pictures if possible
pill organizers, pill alarms, pagers
discuss SE before beginning treatment, anticipate and treat them
avoid drug interactions
discuss with patient in a non-judgmental manner
pharmacist-based adherence clinics
Definition
barriers to adherence and strategies to improve adherence
Term
zidovudine
didanosine
stavudine
lamivudine
abacavir
tenofovir
emtricitabine

chemically similar to nucleosides
must be phosphorylated to be active
interferes with HIV DNA polymerase
Definition
nucleoside reverse transcriptase inhibitors
Term
nevirapine
delavirdine
efavirenz
etravirine

interferes directly with DNA polymerase
no action on mammalian DNA polymerase
no phosphorylation necessary
single mutation leads to CLASS RESISTANCE
Definition
non-nucleoside reverse transcriptase inhibitors
Term
saquinavir
indinavir
ritonavir
nelfinavir
amprenavir
lopinavir/ritonavir
atazanavir
fosamprenavir
tipranavir
darunavir

inhibit viral protease which is required for polypeptide cleavage and viral budding
binds to the active site of HIV-1 protease
results in the formation of immature, non-infectious viral particles
pharmacokinetic boosting with ritonavir is required with many PIs. rationale: CYP3A4 interaction, lower doses, lower pill burden, highly potent
Definition
protease inhibitors
Term
enfuvirtide

synthetic peptide
binds to the HIV-1 transmembrane fusion protein
prevents viral fusion and entry into the cell
SQ injection BID
Definition
fusion inhibitor
Term
maraviroc

CCR5 co-receptor antagonist
prevents HIV from attaching to the surface of CD4 cells with CCR5 receptor
patient must be tested to see if they have the CCR5 receptor
Definition
entry inhibitor
Term
raltegravir

inhibit the activity of the integrase enzyme to prevent HIV DNA from combining with healthy cell DNA
approved for use in treatment naive patients and treatment resistant patients
Definition
integrase strand transfer inhibitor (INSTI)
Term
comorbid conditions
ADRs
drug interactions
pregnancy or pregnancy potential
genotype results
gender and pretreatment CD4 count (if considering nevirapine)
HLA-B*5701 testing (if considering abacavir)
coreceptor tropism assay (if considering maraviroc)
patient adherence potential
convenience (pill burden, dosing frequency, food/fluid considerations)
Definition
factors to consider when selecting initial HIV regimen
Term
never monotherapy -> only exception is zidovudine perinatal prophylaxis
avoid sequential monotherapy: in context of virologic failure never change just one medication
Definition
HIV drug selection principles
Term
2 NRTI + NNRTI
OR
2 NRTI + PI (preferably boosted with ritonavir)
OR
2 NRTI + INSTI
Definition
recommended initial combination for antiretroviral naive patients
Term
advantages:
saves PI and INSTI for future
low pill burden (once daily option)
less lipid SE

disadvantages:
NNRTI resistance in treatment naive patients
low genetic barrier for development of resistance: cross-resistance among NNRTIs
skin rash
drug interactions
Definition
advantages and disadvantages of an initial HIV regimen of 2 NRTI + NNRTI
Term
advantages:
saves NNRTI and INSTI for future use
higher genetic barrier to resistance
PI resistance uncommon with failure (boosted PIs)

disadvantages:
compromises future PI regimens
metabolic complications: dyslipidemia, insulin resistance, hepatotoxicity
GI ADRs
drug interactions (ritonavir especially)
higher pill burden
Definition
advantages and disadvantages of an initial HIV regimen of 2 NRTI + PI
Term
advantages:
saves PI and NNRTI for future
fewer drug related ADRs and lipid changes than efavirenz
virologic response noninferior to efavirenz
no food effect
fewer drug interactions than PI or NNRTI

disadvantages:
less long term experience in ART naive
lower genetic barrier for development of resistance than boosted PIs
no data with NRTIs other than tenofovir and emtricitabine in ART naive patients
BID dosing required
Definition
advantages and disadvantages of an initial HIV regimen of 2 NRTI + INSTI
Term
Efavirenz (NNRTI)
PLUS
Tenofovir (NRTI)
PLUS
Emtricitabine
Efavirenz should not be used during the 1st trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception
Definition
NNRTI based HIV regimen
Term
Atazanavir/Ritonavir
PLUS
Tenofovir
PLUS
Emtricitabine

OR

Darunavir/Ritonavir
PLUS
Tenofovir
PLUS
Emtricitabine

Atazanavir/Ritonavir should not be used in patients who require >20mg omeprazole equivalent per day.
Definition
PI-based HIV regimen
Term
Lopinavir/Ritonavir (PI)
PLUS
Zidovudine (NRTI)
PLUS
Lamivudine (NRTI)
Definition
preferred HIV regimen for pregnant women
Term
Raltegravir (INSTI)
PLUS
Tenofovir (NRTI)
PLUS
Emtricitabine (NRTI)
Definition
INSTI based HIV regimen
Term
Abacavir + Lamivudine + Zidovudine +/- Tenofovir: less efficacy (all NRTIs)
Etravirine (NNRTI) regimens: Abacavir (NRTI) + Didanosine (NRTI) OR Abacavir (NRTI) + Tenofovir (NRTI) - lack of data in treatment naive patients
Darunavir (PI): unboosted no data
Saquinavir (PI): unboosted less efficacy
Stavudine (NRTI) + Lamivudine (NRTI): increased toxicity
Didanosine (NRTI) + Tenofovir (NRTI): high risk of failure, rapid rate of resistant mutations, potential for immunologic non-response/CD4 decline
Delaviradine (NNRTI): less efficacy, TID dosing
Enfuvirtide (fusion inhibitor): no data, BID SQ dosing
Indinavir (PI): unboosted TID dosing with meal restrictions
Indinavir (PI): boosted high incidence of nephrolithiaisis
Nelfinavir (PI): inferior, high incidence of diarrhea
Ritonavir as sole PI: GI intolerance, high pill burden
Tipranavir (PI): boosted less efficacy
Definition
drugs to avoid for initial HIV therapy
Term
obtain CD4 and HIV RNA titers before starting therapy

optimal virologic response is maximal virologic suppression:
virologic suppression - HIV RNA levels < 48
virologic failure - inability to achieve/maintain HIV RNA levels < 200
incomplete virologic response - 2 consecutive HIV RNA levels > 200 after 24 weeks on ARV therapy

check HIV RNA titers in 2-8 weeks after initiation or change in therapy then q3-4 months
always confirm rising titer with 2nd test
Definition
monitoring and goals of HIV therapy
Term
if D/C one med -> D/C ALL meds at the same time
Definition
correct way to D/C HIV meds
Term
antepartum:
combination ART > single-drug regimen
longer duration (begin at 28 weeks gestation) > shorter duration (begin at 36 weeks gestation)

postpartum:
breastfeeding is NOT recommended for HIV infected women
Definition
recommendations for antepartum and postpartum HIV patients
Term
Efavirenz
Definition
what HIV drug should be avoided in the 1st trimester of pregnancy?
Term
Nevirapine (NNRTI) and Lamivudine (NRTI)
Definition
what 2 HIV medications can be added to a pregnant patient or infants regimen in high risk situations?
Term
HIV DNA PCR: tests for viral load where as Western blot and ELISA test for antibodies which will be transferred to the baby from the mother even if the baby is HIV (-)
Definition
what type of HIV test should be used in infants?
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