HIV Flashcards by Peighton Bolt

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

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HIV diagnoses over time

17% decrease in 2020 bc no one was going to the doctor
* gay, bisexual, msm contact= main population affectd

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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

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1 assoc symptom with HIV

Kaposi sarcoma- tongue
Raised erythematous - Herpes 8

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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

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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

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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

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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

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Efavirenz

nnrtis

SE: neuropsychiatric sxs: insomnia, vivid dreaming, dizziness, confusion, hallucinations
NO PREGO

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Nevirapine

nnrtis

Severe rash, hepatitis- occasionally fulminant and fatal
macular papular can lead to SJS or life threatening hepatitis

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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

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Tenofovir alafenamide TAF

nrti

bolded

TAF
SE: GI symptoms, headache, increased creatinine, proteinuria, bone loss

all less than TDF

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Tenofovir disoproxil fumarate TDF

Vemlidy

SE: n.v.d flatulence, headache, renal insuff, bone loss

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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

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Didanosine (Videx)

nrti

SE: peripheral neuropathy, pancreatitis, diarrhea

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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

1. ART should be initiated in all adults living with HIV- regardless of count or stage 2. PRIORITY- all adults with severe or advanced (stage 3 or 4) (count equal or below 350 3. ALL PREGNANT AND BREASTFEEDING WOMEN LIVING WITH HIV 4. 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

1. Biktarvy: Bictegravir/tenofovir alafenamide/Emtricitabine 2. 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

1. Atazanivir (PI) (reyataz)- careful with Statins, **SE: GI, CNS, IRS, metabolic** 2. Darunivir (PI) (prezista) 3. Raltegravir (II)- low drug interactions: GI, headache, fever 4. Maraviroc (CCR5 co-R antag)- cough and fever

pharmacokinetic enhancers | boosting agents

1. Cobicistat= **CYP3A inhibitor**- increases systemic exposure 2. Ritonavir= **CYP3A4**- in many combo products to augment systemic exposure

Goals of tx:

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

1. NRTIS * abacavir * emtricitabine * lamivudine * Tenofovir disoproxil fumarate * zidovudine= alternative= iv during labor 2. PI * atazanavir/ritonavir * darunavir/ritonavir 3. 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

1. list 6 classes of HIV TX 2. details of clinical approach to HIV TX 3. basics of ART 4. 2 drug combos w NRTI tx 5. SE and interactions for ART 6. Boosting agents and rationale for use 7. immune reconstitution syndrome explain-> clinical relevance 8. Basics of post exposure prophylaxis for HIV