HIV Flashcards
Human immunodeficiency virus
HIV
- HIV-1- most common type with AIDS- most tx target
- HIV-2- mostly West africa and india
Main target- immune system- immunodeficiency
cd4, helper t cells, macrophages, dendritic cells
HIV diagnoses over time
17% decrease in 2020 bc no one was going to the doctor
* gay, bisexual, msm contact= main population affectd
HIV mech
- HIV infects cells by using the CD4 molecule as a receptor and various chemokine receptors as coreceptors. MUST also bind to these coreceptors for entry into the cell. Fusion w/ CD4 and gp120
- The gp120 envelope glycoprotein binds to CD4, which leads to conformational change that produces a new recognition site on gp120 for those coreceptors (induces changes in gp41 that expose the fusion peptide).
- The peptide inserts into the cell membrane of the target cells leading to the fusion of the virus and host cell. Virus core containing the HIV genome is able to enter the cell. hiv reverse transcriptase, integrase, and other viral proteins, enter cell
- Once it enters the cell, the RNA genome undergoes reverse transcription and leads to double stranded complementary DNA. Integrates into the host DNA. It can stay silent for months or years or form new viral RNA and proteins. viral dna formed by reverse transcripton then transported and integrated into host dna
- In the case of most CD4+ T cells, viral replication and shedding leads to cell lysis. viral rna and proteins move to surface and released
1 assoc symptom with HIV
Kaposi sarcoma- tongue
Raised erythematous - Herpes 8
Antiretroviral therapy
ART therapy
Each class targets a different step in life cycle:
use of agents in clinic is dictated by:
* ease of use
* SE
* efficacy based on clinical evidence
* clinician and pt preference
* resistance, AE, Pregnancy, infection with Hep B and C
Drug classes for ART therapy
- Non nucleoside reverse transcriptase inhibitors (NNRTIs)
- Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- Protease inhibitors
others: fusion inhibitor, entry inhibitors, integrase strand transfer inhibitors
COMBOS IS HALLMARK OF TX
KNOW NUMBERED
Drug classes for ART therapy
- Non nucleoside reverse transcriptase inhibitors (NNRTIs)
- Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- Protease inhibitors
others: fusion inhibitor, entry inhibitors, integrase strand transfer inhibitors
COMBOS IS HALLMARK OF TX
KNOW NUMBERED
Non nucleoside reverse transcriptase inhibitors NNRTIS
Efavirenz and Nevirapine
MOA: bind directly to HIV1 reverse transcriptase-> allosteric inhibition of RNA and dna dependent dna polymerase activity
2nd gen= higher potency, and reduced SE (Doravirine, etravirin vs. Delavirdine, efavirenz)
Testing: genotypi testing since there could be primary resistance
No cross resistance btwn NNRTI and NRTIS
ALL ARE SUBSTRATES FOR CYP3A4-> can be inducers, inhibitors, or mixed
binding site differ from NRTIS-> doesnt compete with triphosphates
or need active phosphorylation
Efavirenz
nnrtis
SE: neuropsychiatric sxs: insomnia, vivid dreaming, dizziness, confusion, hallucinations
NO PREGO
Nevirapine
nnrtis
Severe rash, hepatitis- occasionally fulminant and fatal
macular papular can lead to SJS or life threatening hepatitis
Nucleoside/nucleotide reverse transcriptase inhibitors
NRTIS
Tenofovir Alafenamide TAF, Didanosine (Videx), Stavudine, Tenofovir disoproxil fumarate (TDF)-Vemlidy
MOA: interrupts HIV rep via competitive inhibition of reverse transcriptase= termination of DNA chain
SE: mitochondrial toxicity -> peripheral neuropathy, lactic acidosis can be fatal= Sodium bicarb tx
Tenofovir alafenamide TAF
nrti
bolded
TAF
SE: GI symptoms, headache, increased creatinine, proteinuria, bone loss
all less than TDF
Tenofovir disoproxil fumarate TDF
Vemlidy
SE: n.v.d flatulence, headache, renal insuff, bone loss
Abacavir
NRTI
Ziagen
Test to rule out HLAB-27 prior bc increased hypersensitivity reactions
SE: possible increase in MI, rash, hypersens reaction, nausea
avoid alcohol
Didanosine (Videx)
nrti
SE: peripheral neuropathy, pancreatitis, diarrhea
Stavudine
nrti
SE: peripheral neuropathy, pancreatitis, rapid neuromusc weakness- rare
Zidovudine (AZT) (Retrovir)
SE: macrocytic anemia, neutropenia, nausea, headache, insomnia
Avoid: concurrent with Stavudine and mylosuppressive drugs (ganciclovir or ribavirin)
Can be used pediatrics
Protease inhibitors PIS
Atazanavir, Indinavir
MOA: prevent processing of viral proteins into functional conformations-> produce immature or noninfectious viral particles
Genotypic alterations-> resistence so MONOTHERAPY NOT REC
SE: GI INTOLERANCE- NVD
lipodystrophy-> hyperglycemia/hyperlipidemia-> may require lipid lowering agents
syndrome of tredistrubution and accum body fat-> specifically w/ nrtis- central obesity, dorsocervical fat enlargemetn (buffalo hump), peripheral facial wasting, breast enlargment, cushingoid appearance
cardiac conduction abn: PR and AT elongation
Metab via CYP3a4
Atazanavir
PIS
SE: Nausea, rash indirect hyperbilirubinemia, diarrhea, elevated liver enzymes
Indinavir
PSI
SE: Nephrolithiasis, indirect hyperbilirubinemia, nausea, diarrhea, headache, possible MI
Fusion Inhibitors
Enfuvirtide
MOA: blocks HIV entry into cell-> binds gp41 subunit of viral envelope glycoprotein
SQ injxn: ONLY ANTIRETROVIRAL LIKE THIS
AE: local injxn site rxn, potential: insomnia, headache, nd, eosinophilia, increased bacterial pneumonia
NO SIGNIFICANT DRUGDRUG INTERACTIONS
Entry inhibitors
- Idalizumab- monoclonal ab that binds CD4 receptor and blocks HIV entry- FOR MULTIDRUG RESIS HIV- CAN BE IN COMBO- nvd
- Maraviroc-CCR5-tropic HIV1- binds to CCR5
SE: cough, pyrexia (fever), rash, hepatitis
Integrase strand transfer inhibitors
INSTIS
- Bictegravir
- Dolutegravir
- Elvitegravir
- Raltegravir
MOA: binds to integrase-> inhibits ssstrand stransfer thus interfering with integration into host dna
AE: n/v, CK/LFT elevations, headache
First line regimen-> bc high genetic barrier to resistance
DECREASES VIRAL LOAD MORE RAPIDLY THAN ANY OTHER ART
Clinical approach to HIV tx
- risk- benefit
- cost
- adherence- once begun, tx is forever
- pill burdern- try to fix by once a day
- patient readiness trumps cd4 count
- high risk pts should begin tx regardless of count symptomatic, pregnant, liver disease, high viral load
- Naive vs non naive patients
Recommendations for HIV
- ART should be initiated in all adults living with HIV- regardless of count or stage
- PRIORITY- all adults with severe or advanced (stage 3 or 4) (count equal or below 350
- ALL PREGNANT AND BREASTFEEDING WOMEN LIVING WITH HIV
- ALL CHILDREN LIVING WITH HIV
ART: antiretroviral therapy
rules
Usual therapy is 3 or more combos:
* 2x NRTIS plus a INSTI or NNRTI or PI with pharmacokinetic enhancer
2 drug regimen: Dolutegravir + Lamivudine
* reduces viral load till undetectable
* Cautious with antiherpetics
* GI, fatigue, cns, fatty liver sx improve after 1 month
Possible initial tx regimens innaive pt
- Biktarvy: Bictegravir/tenofovir alafenamide/Emtricitabine
- Dovato: Dolutegravir/Lamivudine
Biktarvy
Bictegravir/Emtricitabine/Tenogovir alafenamid
BBW: severe acute exacerbations of hepatitis B
BUT ONE PILL A DAY
AE: nd, headache
Dovato
dolutegravir/lamivudine
AE: headache, nd, trouble sleeping, tiredness, anxiety
Agents added to initial regimen
if viral load not going down
- Atazanivir (PI) (reyataz)- careful with Statins, SE: GI, CNS, IRS, metabolic
- Darunivir (PI) (prezista)
- Raltegravir (II)- low drug interactions: GI, headache, fever
- Maraviroc (CCR5 co-R antag)- cough and fever
pharmacokinetic enhancers
boosting agents
- Cobicistat= CYP3A inhibitor- increases systemic exposure
- Ritonavir= CYP3A4- in many combo products to augment systemic exposure
Goals of tx:
<reduce HIV infxn- morbidity, prolong survival
< improve quality of life
< restore and preserve immunologic fxn
<maximally suppress viral load
<prevent vertical HIV transmission
Immune reconstitution inflammatory syndrome
- inflammatory rxn occurs after initiation of antiretroviral tx- secondary to rapid increase in CD4 count
- SXS: fevers, sweats, malaise, unusual presentations of opportunistic infxn
- cmv retinitis- vitreitis
- M. avium- focal, suppurative lymphadenitis
- TB- worsen new with new pulmonary infiltrates
- diag: of exclusion
- TX: conservative and supportive with corticosteroids for severe
- CONTINUE ART THERAPY UNLESS LIFE THREATENING
high ag load + immune cell dysfunction + ART initiation= excess proinflammatory cytokine activity-> IRIS
hiv + tb+ART
cause giant lymphnode swellings? that will go away
Pregnancy and HIV
- NRTIS
* abacavir
* emtricitabine
* lamivudine
* Tenofovir disoproxil fumarate
* zidovudine= alternative= iv during labor - PI
* atazanavir/ritonavir
* darunavir/ritonavir - II- Dolutegravir should not be used in 1st trimester due to possible increased risk of neural tube defects
Pre exposure prophylaxis
PREP
To prevent sexual acquisition of HIV
RF: MSM, promiscuous heterosexual, sexually active transgender, IV drug use
Truvada= emtricitabine and tenofovir disoproxil fumarate
Descovy= emtricitabine and tenofovir alafenamide
Post exposure prophylax for health care workers
intact skin or urine source do not need PEP
must be started w.in 72 hours-> risk of transmission from needle stick with blood from hiv pt is 1:300
HIV 3-drug PEP regimen- given 28 days
1. Raltegravir
2. Dolutegravir (DTG)
3. Truvada
testing at: 0, 6, 12 weeks
Post exposure prophylaxis: non occupational
28 days
1. Tenofovir w/
2. emtricitabine
3. either Raltegravir or Dolutegravir
Summary
- list 6 classes of HIV TX
- details of clinical approach to HIV TX
- basics of ART
- 2 drug combos w NRTI tx
- SE and interactions for ART
- Boosting agents and rationale for use
- immune reconstitution syndrome explain-> clinical relevance
- Basics of post exposure prophylaxis for HIV
