HIV infection 1 & 2 Flashcards
(115 cards)
1
Q
As a general rule, combination antiretroviral therapy (ART) consists of __________ active agents from at least ____ classes
A
two or three
2
2
Q
HIV has been managed as a _____ disease
A
Chronic
3
Q
-Glycoprotein 120 (gp120) binds to ___ receptors on T cells, macrophages, and dendritic cells
-The primary target cell of HIV is the CD4 _________ = a key component of _____ immunity
-Infected CD4 cells are impaired from normal functions, and used for ______ replication–> ultimately destroyed by a cytolytic effect
A
CD4
T helper/inducer lymphocyte
cell-mediated
Viral
4
Q
Routes of HIV transmission
A
- Exposure of mucous membrane or damaged tissue to infected body fluids (through sexual contact; most common)
- Blood stream exposure to infected body fluids (IV drug use)
- Mother-to-child (greatly reduced due to prenatal screening and treatment)
5
Q
T/F: HIV is found in breast milk
A
TRUE
6
Q
HIV (is/is not) found in urine, feces, sweat, tears
A
Not; so general contact is not a problem
7
Q
What are the 3 stages of HIV infection?
A
- Acute Retroviral syndrome
- Chronic HIV infection (asymptomatic)
- Acquired immunodeficiency syndrome=AIDS (symptomatic)
8
Q
What happens in the acute retroviral syndrome stage?
A
-Flu-like illness
-Viral load > 10 million copies/ml
-Virus is seeding in lymph nodes and thymus (makes a seeding reservoir) –> tissues become difficult to access which is why HIV is not a curative disease
-Lasts weeks
9
Q
What happens in chronic HIV infection?
A
-Consists of stage 1 or 2 (live here for years)
-Antibodies have developed against HIV, but this is not enough for most people
-A set point is reached 3-6 months after initial infection –> a higher set point means that CD4 cells decline faster
10
Q
What happens during AIDS?
A
-Once CD4 cells fall below 200
-Most likely for opportunistic infections to occur
11
Q
Screening recommendations for HIV
Testing is________
A
-Patients aged 13-64 in any healthcare setting
-All pregnant women during each pregnancy ASAP (repeat in 3rd trimester)
-All pts starting TB tx
-All pts attending STD clinics
*Testing is opt-out: “you will be tested for HIV today unless you request otherwise”
12
Q
When does HIV RNA (plasma) detect HIV?
A
detectable ~10 days after initial infection (NAAT)
13
Q
When does HIV-1 p24 Antigen become detectable?
What test detects these?
What does this tell us?
A
~15 days
-4th generation detects these
-p24 is a core HIV protein = detects acute infection
14
Q
When is HIV antibody detected?
A
~23 days after initial infection
15
Q
What is the seroconversion window?
A
Time is takes for the conversion of antibodies
**No test is available for detection before 10 days
16
Q
Diagnosing HIV
A
-Positive results from a multi-test algorithm
-Initial and supplemental tests must be different (Must have 2nd test to confirm)
-Positive virologic test (viral load; qualitative HIV NAT)
17
Q
Which HIV is more common: 1 or 2?
A
1
18
Q
What is OraQuick?
A
HIV rapid test available OTC
-3rd gen tests that uses oral fluid (pts swab between check & gum line –> flip swab to run under the bottom gum line), then place in developer solution for 20 minutes
19
Q
Counseling for OraQuick
A
-Pts with reactive results should seek medical provider for confirmatory testing (this is a preliminary screen)
-Pts with non-reactive results should be advised on the seroconversion window (3 months) and repeat the test if a risk event occurred within the window period
-Methods for risk reduction and prevention
20
Q
HIV surrogate markers
A
CD4 lymphocyte cell count
HIV RNA PCR (viral load)
21
Q
What is the CD4 T lymphocyte cell count used for?
A
Primary marker of immunocompetence
-Most useful BEFORE tx initiation
-Lower levels are indicative of a more compromised immune system (check if ART is needed)
22
Q
What is HIV RNA PCR used for?
A
-Assessing the effectiveness of therapy
-Most useful after initiation of therapy
-Higher baseline levels are predictive of faster disease progression
-Tested Q6mos for the rest of the patient’s life
23
Q
CD4 count in stage 0
A
Acute HIV (<6 months): staged by independent criteria
24
Q
CD4 count stage 1
A
Greater than or equal to 500 cells/mm3
25
CD4 count stage 2
200-499 cells/mm3
26
CD4 count stage 3
AIDS!!!!!!
<200 cells/mm3 or OI diagnosis
**AIDS diagnosis will not go away, but CD4 count will improve with ART
27
Nucleos(t)ide reverse transcriptase inhibitors (NRTS) MOA
-Synthetic purine and pyrimidine analog which result in elongation termination of growing proviral DNA chain (lacks 3'-OH)
28
NRTI Class ADR
Mitochondrial toxicity and lactic acidosis
29
Which NRTIs result in less frequent ADR
TEAL
Tenofovir, emtricitabine, abacavir, lamivudine
**Don't have as much affinity for human DNA polymerase
30
Precautions with NRTI
Renal dose adj (except abacavir)
31
Non-nucleos(t)ide reverse transcriptase inhibitor MOA
Bind to allosteric site of RT enzyme reducing functionality
32
NNRTI class ADR
RASH
Usually within the first 4 weeks of tx; D/C if it lasts > 4 weeks or gets worse
33
Precautions with NNRTI
-Use with caution in pts with hepatic impairment
-LOTS of drug interactions exist
-Easy to develop resistance (why they are rarely used)
34
MOA of protease inhibitors
Inhibit the action of viral protease preventing the assembly, maturation, and release of new virions
35
Protease inhibitors class ADR
GI intolerance (N/V/D)
Insulin resistance
Lipodystrophy
36
Precautions with protease inhibitors
-Many are not recommended in severe hepatic impairment
-LOTS of drug interactions
-Highly favorable resistance profile (especially when boosted), but greater pill burden
37
What is boosting?
What class of drugs are they used with?
-Incredibly potent CYP3A4 inhibitors to inhibit the metabolism of the protease inhibitor --> lengthens the half-life, reduces the drug dose & frequency, and increases systemic circulation
-Protease inhibitors
38
Which 2 drugs are used as boosters?
Ritonavir 100-200 mg QD-BID
Cobicistat 150 mg QD
39
Do boosters have any anti-HIV activity?
NO; ritonavir does at higher doses, but not the dose used in boosting
40
Integrase strand transfer inhibitors (INSTIs) MOA
Inhibits HIV integrase, preventing the proviral DNA integration into the host cell genome
41
INSTI class ADR
Weight gain
42
Precautions with INSTIs
-Fewer drug interactions than NNRTIs and PIs (except elvitegravir which must be boosted)
-Elvitegravir must be given with ritonavir
-Resistance can easily develop to 1st gen INSTIs (raltegravir & elvitegravir), but 2nd gen (dolutegravir & bictegravir) have resistance profile on par with boosted PIs
43
Attachment inhibitor MOA
-Fostemsavir is a prodrug of temsavir
-Temsavir binds gp120 on surface of HIV, blocking attachment to CD4 T-cell co-receptor
44
Precautions with attachment inhibitors
-Contraindicated with strong CYP3A4 inducers as coadministration results in significant decreases in temsavir concentrations
-Rarely used (FDA approved for last line ONLY)
45
Post-attachment inhibitor MOA
Binds D2 domain of CD4 T-cell co-receptor and interrupts the post-attachment steps required for entry of HIV into host cell
46
Precautions with post-attachment inhibitors
-In-clinic IV administration after dilution in 250 ml of NS Q2wks
-No drug interactions
-Rarely used (reserved for last line tx)
47
Chemokine coreceptor 5 (CCR5) antagonist MOA
-Binds CCRF5 on the CD4 cell surface, blocks the binding of gp120, and prevents entry of HIV into the host cell
48
Precautions with CCR5
-Before tx can be considered, a tropism assay must be performed
***ONLY active against CCR5-tropic strains of HIV (must exclusively be CCR5; not mixed)
-CYP3A4 substrate (watch dosing)
49
Capsid inhibitor MOA
-Binds interface between capsid protein (p24) subunits
-Interferes with multiple steps of the viral lifecycle (uptake of proviral DNA, virus assembly & release, capsid core formation)
50
Precautions with capsid inhibitors
-Half-life is 8-12 weeks (residual concentrations remain for 12+ months)
-CYP3A4 substrate
-Currently ONLY approved for pts with multi-drug resistant infection who are failing their antiviral regimen
51
Dosing schedule of capsid inhibitors
SQ Q6mos
**usually needs to be co-administered with a once daily drug, so not much benefit from it being Q6mos
52
Benefits of HIV tx
-Reduces HIV-related morbidity & mortality (reduces immune activation & inflammation)
-Reduced HIV transmission (sexual & perinatal)
-Suppresses viremia (prevents selection of drug resistance-associated mutations; preserves & improves CD4 count)
53
Limitations of HIV tx
-NOT curative
-Interruptions in tx have serious consequences
1. Rebound viremia: risk of resistance
2. Worsening immune function
3. Increased morbidity/mortality
-MUST be continued indefinitely (lifelong)
54
When is ART initiated in HIV pts?
-Recommended for ALL HIV-infected pts regardless of CD4 count
-Should be initiated immediately (or ASAP) after diagnosis
-Early initiation is particularly important for
1. AIDS-defining conditions (except meningitis from TB or cryptococcus)
2. Acute/recent HIV infection
3. Pregnancy (bc 2 lives at stake)
55
Why do we not start ART immediately for meningitis from TB or cryptococcus?
To prevent IRIS; want to get infection a bit more controlled
56
What ART tx to start?
1. Monotx & most dual-ART drug combos (are/are not) recommended for initial tx -- why or why not?
2. Which classes are used?
1. Are not; because this causes incomplete/transient viral suppression & development of ART resistance
2. 2 NRTIs in combo with a 3rd active ARV from 1 of 3 drug classes
a. INSTI (recommended for most pts)
b. NNRTI
c. PI boosted with PK enhancer (ritonavir/cobicistat)
Data also support 2 drug regimen (dolutegravir + lamivudine) for initial tx
57
Recommended initial tx for most people with HIV
(no history of long-acting cabotegravir use for HIV prevention)
1. INSTI + 2 NRTI
a. Bictegravir/tenofovir alafenamide/emtricitabine (Biktarvy)
b. Dolutegravir + TAF/TDF + emtricitabine/lamivudine
2. INSTI + 1 NRTI
a. Dolutegravir/lamivudine
58
What must be done before initial tx with dolutegravir/lamivudine?
1. Genotype: to look for baseline resistance
2. Ensure there is not active HepB infection
3. HIV RNA < 500000 copies/ml
4. Ensure ART does not need to be started before HIV genotype results
59
Recommended initial tx in INSTI-based regimen
Dolutegravir/abacavir/lamivudine (If HLA-B*5701 is negative and without chronic HBV co-infection)
60
Recommended initial tx in PI-based regimen if hx of cabotegravir exposure
1. (Darunavir/cobicistat or darunavir/ritonavir) + (TAF or TDF) + (emtricitabine or lamivudine)
2. (Darunavir/cobicistat or darunavir/ritonavir) + abacavir/lamivudine (co-formulation) **If HLA-B*5701 is negative
61
Recommended initial tx in NNRTI-based regimen
1. Doravirine/TDF/lamivudine (co-formulated)
2. Doravirine + TAF/emtricitibine
3. Rilpivirine/TAF/emtricitibine (co-formulated) if HIV RNA < 100000 copies/ml & CD4 > 200 cells/mm3
62
ALWAYS run a ______ screen before initiating any tx
Drug interaction
63
ARV drug interaction principles:
Boosted PIs are strong _______
CYP3A4 inhibitors
64
ARV drug interaction principles: NNRTIs are _____
CYP3A4 inducers
**Rilpivirine & doravirine are not inducers -- only substrates
65
ARV drug interaction principles: INSTIs are _____
UGT1A1 substrates
66
Maraviroc, Fostemsavir, and lenacapavir are ____
Substrates of CYP3A4
67
Drug interactions with acid reducers
1. Separate antacids from PO INSTIs by 6 hours
2. NEVER give raltegravir with Al or Mg
3. Atazanavir and PO Rilpivirine are reduced by acid reducers; rilpivirine is C/I with PPIs
68
Drug interactions with benzodiazepines
With protease inhibitors & cobicistat, preferred benzos are LOT (lorazepam, oxazepam, temazepam)
69
Drug interactions with CCS
With protease inhibitor & cobicistat, beclamethasone is preferred (NO OTC NASAL FLUTICASONE)
70
Drug interactions with statins
With protease inhibitors and cobicistat, low doses of atorvastatin, rosuvastatin, pitavastatin, or pravastatin are preferred **b/c less reliant on 3A4**
Dose may need INCREASED with NNRTIs
71
Drug interactions with biguanides
Dolutegravir increases metformin, so a dose decrease of metformin may be necessary
72
Drug interactions with PDE5 inhibitors
With protease inhibitors and cobicistat, use very LOW doses Q48-72H
73
Drug interactions with polyvalent cation supplements (multivitamin/prenatal vitamins)
With integrase inhibitors, space these apart by 6H.
Co-admin of Ca/Fe with dolutegravir or bictegravir must be taken WF
74
Polymorphic resistance
Naturally occurring variants in the absence of therapy -- not associated with decreased susceptibility to ART
75
Major resistance
Amino acid substitutions (point mutations) --> reduced susceptibility to 1 or more ART posing a survival advantage
76
Minor resistance
Accessory mutations which have little to no effect on drug susceptibility, but may increase the replication fitness of a virus with a major mutations
**May need several minor to have a reduced impact
77
Resistance associated mutations: transmitted
1. Obtained with initial HIV infection or superinfection (transmitted from initial person to 2nd person)
2. Rate is location-dependent
78
Resistance-associated mutations: acquired
1. Inadequate adherence (most common)
2. Inadequate dosing (prescriber error)
3. Inadequate drug concentration (drug interaction or malabsorption)
79
Adherence vs resistance
0% adherence = inadequate drug pressure to select resistant virus
100% adherence = complete viral suppression
40-80% adherence = drug pressure selects resistant virus
80
Implication of resistance-associated mutations (RAMs)
-May limit the selection of effective first-line therapeutic options
-Increases time to virologic suppression
-Increases risk of tx failure
-Decreases the efficacy or pre- and post- exposure prophylaxis
-Resistant strains can return to resting state - 'archive' (If 'R' strains develop, we can never think of them as going away bc they can be reactivated)
-Resistance is CUMULATIVE (if it has ever existed, then consider it to be permanent)
81
Genetic barrier to resistance: NRTI
Low genetic barrier (requires 1-2 mutations to take them out)
82
Genetic barrier to resistance: 1st gen INI
Low genetic barrier (only requires 1 mutation to take them out)
83
Genetic barrier to resistance: 2nd gen INI
High genetic barrier (takes 3 mutations to take them out)
84
Genetic barrier to resistance: protease inhibitors
High genetic barrier of resistance
85
Resistance testing should be performed ___ & ____
At entry to care
Virologic failure/suboptimal viral response
86
What should happen when there is virologic failure or suboptimal viral response?
1. Genotype is recommended when failing 1st or 2nd regimen (looks at RT and protease genes initially)
2. Sequence integrase if failing INSTI-based regimen
3. Specimen must contain > 500 copies/ml of virus for best results, but should still be considered if > 200 copies/ml
4. Phenotype should be considered in pts with extensive tx hx ($$$; if failed 3rd/4th regimens)
87
What drug class is genotyped to check RT sequencing?
NRTI & NNRTI
88
What drug class is genotyped to check protease gene sequencing?
Protease inhibitor
89
What is virologic failure?
Inability to achieve/maintain suppression or viral replication to a viral load <200 copies/ml
90
Common reasons for virologic failure
1. Comorbidities impacting adherence (active substance abuse, psych disease, neurocognitive deficits)
2. Presence of resistance-associated mutations (transmitted & acquired)
3. Incomplete adherence to meds & clinic appts
4. ADR
5. High pill burden/dosing frequency
6. Drug interactions
91
Managing virologic failure
1. Assess adherence & any potential interactions
2. If failure persists, perform resistance testing
a. If no 'R' identified, reinforce adherence & restart old regimen
b. If 'R' identified, reinforce adherence & construct new regimen with:
-2 fully active drugs if at least one with a high resistance barrier is included (eg: dolutegravir or boosted-darunavir)
-3 fully active drugs
3. Expert consultation advised
92
Regimen switches
1. Switch when virologically ____
2. Monitor closely for the next ______ to assess for tolerability and viral rebound
Suppressed
4-8 weeks
93
Unexposed prevention
Condoms
STD tx
Circumcision
94
Pre-exposure prevention
PrEP (tabs, injectable, other dosage forms)
95
Post-exposure prevention
PEP (tabs for 28 days)
96
Infected pt
Treatment (TasP, U=U)
97
What is undetectable equals untransmittable?
U=U
1. Maintaining plasma HIV RNA < 200 copies/ml with ART prevents sexual transmission of HIV to sexual partners
2. Another form of prevention should be used for at least the first 6 mos & until HIV RNA < 200 copies/ml
98
Non-pharmacologic prevention of HIV
1. Latex and polyurethane male/female condoms
2. Seropositioning
3. Water-based lubricants & spermicide that do not contain nonoxynol-9
4. Circumcision
5. Syringe exchange programs
6. Frequent testing
99
What is PrEP?
Use of antiviral agents in HIV-negative persons at high risk for HIV acquisition for the purpose of HIV prevention
*Not lifelong (reassess risk regularly)
100
Indicated groups for PrEP
1. Recent bacterial STI
2. Condomless vaginal/anal sex with a partner of unknown HIV status
3. HIV positive partner
4. Injection drug use with sharing needles
5. Any survival/transactional sex
6. Desire to conceive w/ partner that is HIV positive
7. Anyone who requests it
101
Contraindications for PrEP
1. HIV infections (b/c 1-2 agents will be inefficient)
2. Weight < 77 lbs
3. Estimated CrCl
a. < 60 ml/min TDF/FTC
b. <30 ml/min TAF/FTC
4. Possible HIV exposure within the past 72H (offer PEP instead)
102
PrEP regimens: PO QD
1. Emtricitabine/TDF 200/300 mg PO QD for all risk groups
2. Emtricitabine/TAF 200/25 mg PO QD for men & transgender women who have sex with men
103
PrEP regimens: Oral on demand
***NOT FDA APPROVED***
Emtricitabine/TDF 200/300 mg PO for men who have sex with men
2t PO 2-24H prior to sex, then 1t PO 24H after 1st tab was taken; continue 1t PO QD until 48 hours after last sexual encounter
104
PrEP regimens: injection
1. Cabotegravir 600 mg IM (gluteal muscle)
*Optional: CAB 30 mg PO QD x 30d as oral lead in before 1st injection to assess tolerability
2. Give 2nd dose 1 month after the first dose, then Q2mos thereafter
105
Residual concentrations of cabotegravir may remain in systemic circulation for prolonged periods (up to ____ or longer)
--There is a risk of CAB resistance if infected with HIV during this time.
--Patients must be aware that for 12 months after last injection, they will have _____ doses of HIV, so they should use _____
12 months
Low
Another form of HIV protection
106
Lab screening prior to PrEP for all patients
1. HIV test within 1 week before starting PrEP (ideally HIV Ag/Ab) b/c if (+), we need to initiate ART
2. HIV RNA (if possibly infected within the past 2-4 weeks)
3. STI testing: gonorrhea/chlamydia, syphilis, Hep C Ab, Hep A IgG
107
If considering oral PrEP, in addition to other lab screenings, what else should be obtained?
1. Creatinine (for estimated CrCl)
2. Hep B sAb, cAb, Ag
3. For TAF/FTC: cholesterol and TG
108
Follow up/monitoring for oral PrEP
1 month: ensure pt is still HIV uninfected, then at least Q3mos --> HIV Ab/Ag, HIV RNA, screen for STI, pregnancy test
Q6mos: CrCl for pts >/= 50 or eCrCl < 90
Q12mos: Cholesterol & TG levels. HCV Ab for MSM, transgender women, people who inject drugs
109
Follow up/monitoring for injection PrEP
1 month: HIV RNA
Q2mos: HIV Ag/Ab & HIV RNA. Pregnancy test as appropriate.
Q4mos: HIV RNA, STI testing
***COMPLETE NAAT BEFORE EVERY INJECTION TO ENSURE PT HAS NOT ACQUIRED HIV SINCE LAST INJECTION
110
PrEP key takeaways
1. When used as directed, it is highly effective for preventing HIV (>90%)
2. With daily TDF/FTC, max blood & rectal tissue drug levels are reached after 7 days & vaginal tissue after 12 days
3. If planning to stop oral PrEP, continue for 28d after last potential HIV exposure
4. If a potential high-risk HIV exposure occurs while NOT on PrEP, start PEP (within 72 hours) x 28d
111
When is post-exposure prophylaxis recommended?
-After accidental HIV exposure has occurred
-Occupational (needlestick; blood/body fluid splash)
-Non-occupational (sexual assault; condom break)
112
PEP considerations
-Exposures to other fluids/tissues << blood
-HIV status of source patient (if known) should be determined --> if source pt is negative, D/C PEP & no follow up is needed
113
PEP regimen
Emtricitabine/TDF 200/300 mg PO QD x 28d + (raltegravir 400 mg PO BID x 28d -OR- dolutegravir 50 mg PO QD x 28d)
**Initiated ASAP
**Must be initiated within 72H or little benefit will be obtained
114
PEP monitoring
1. Rapid testing @ baseline: IF (+), do NOT initiate PEP; start ART
2. Repeat testing at 4-6 weeks & 3 months (preferably 4th gen)
115
PEP counseling
-Use precautions (barrier contraception, avoidance of blood/tissue donation, pregnancy, and breastfeeding) to prevent secondary transmission (esp during first 6-12 weeks)
-Possible drug toxicities
-Importance of adherence
-If at ongoing risk, evaluate for PrEP indefinitely
