HIV/AIDS Flashcards
Describe HIV routes of transmission
Sexual-Anal or vaginal (hetero/homosexual transmission; semen, vaginal fluid) *oral sex - rare*
Blood-to-blood contact & Intravenous Drug User (IVDU)
Perinatally (maternal-child transmission, breast milk)
Understand pathogenesis of HIV
HIV is a retrovirus which invades CD4+ T-lymphocytes cells
CD4+ = immune cells responsible for orchestrating and coordinating immune response
Thus HIV patients cannot fight off infection as easily because the CD4+ has been hijacked
HIV is a retrovirus (contains 2 single strands of RNA) and it LACKS machinery needed for self replication (obligatory PARASITES)
In order to replicate HIV virus needs to transcribe its RNA into DNA
The enzyme employed for this process is called Reverse transcriptase = converts single stranded RNA into double stranded DNA
Retroviruses cannot self-replicate, they are intracellular parasites
Retroviruses carry genetic material in RNA rather than DNA
HIV targets CD4 T cells b/c the surface of the T cells provide an attachment point for HIV
gp120 is the primary surface receptor (glycoprotein) on the HIV envelope and it attaches to the T cell
Infected CD4 cell reproduces, inadvertently producing more viral HIV copies
3 ENZYMES are needs for HIV to penetrate the T cell and replicate:
Reverse transcriptase (step 3, 4 in replication cycle)
Integrase (step 5 in replication cycle)
Protease (step 10 in replication cycle)
Once HIV infects a CD4 cell, it DIES within 2 days
Understand replication cycle of HIV
1: Attachment:
gp120 on the HIV envelope attaches to a CD4 host protein
Other host proteins (aka co-receptors) secure the attachment (ie. CCR5, CXCR4)
Drug class that works here: CCR5 Antagonist
2: Fusion of HIV lipid bilayer with host lipid bilayer, release of HIV RNA into host cell
Drug class that works here: Fusion Inhibitors
3: DNA Synthesis/Reverse transcriptase
4: Replication/Integration
5: Integration (DRUG TARGET)
6: Transcription
7: Translation
8: Migration & Assembly
9: Budding off
10: Processing by HIV protease (DRUG TARGET)
CDC Definition of AIDS
A syndrome in which the individual is HIV positive and has either:
- CD4 counts below 200 cells/mL
- AIDS-defining illness
Pneumocystis pneumonia
Cytomegalovirus retinitis
Disseminated histoplasmosis
Tuberculosis
Kaposi’s sarcoma
Symptoms of HIV
Symptoms fall into 3 categories:
Immunodeficiency, Autoimmunity & Neurologic Dysfunction
Here is what to look for:
Fever
General malaise and achiness
Fatigue
Night sweats
Sore throat
Gastrointestinal symptoms––anorexia, nausea, vomiting, heartburn, diarrhea
Swollen lymph nodes
New rash
Headache
Decreased WBC and/or CD4+ counts
HART Treatments
HAART (highly active antiretroviral therapy) or CAR (combined retroviral therapy)
Decreases plasma HIV levels
Delays or reverses loss of immune fxn
Decrease certain AIDS-related complications
Preserves health, prolongs life, decreases HIV transmission
$$$$$$$, lifelong
NOT curative
Patients who should receive HAART
Patients with advanced (symptomatic HIV)
Patients with a history of AIDS-defining illness
Pregnant women
Patients with HIV-associated nephropathy, active Hep B infection, active cardiovascular disease
Patients with:
CD4 counts <500 cells/mm3 (or a rapid decline in CD4 count)
High viral load (>100,000 copies of HIV RNA)
Describe briefly the mechanism of action of HAART drugs
TWO MECHANISMS OF ACTION:
INHIBIT HIV ENZYMES (reverse transcriptase, integrase, protease)
BLOCK HIV ENTRY INTO CELLS (fusion inhibitors, CCR5 antagonists)
5 categories of HAART drugs
1. Reverse transcriptase inhibitors (2 sub types)
1.1 NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors)
Drug Examples: Zidovudine (Retrovir, ZDV), Tenofovir, Abacavir (Ziagen)
MOA:
chemical relatives of naturally occurring nucleosides and nucleotides (DNA building blocks)
suppresses synthesis of viral DNA by reverse transcriptase (prematurely terminates growing DNA strand)
Needs intracellular conversion to be active
Common SEs: RARE lactic acidosis, severe hepatomegaly (fatal)
*see STEPS 3 & 4 of replication cycle
1.2 NNRTIs (non-nucleoside reverse transcriptase inhibitors)
Example. Efavirenz (Atripla)
NOT analogs of natural nucleosides
MOA:
NO structural relationship with naturally occurring nucleosides (DNA building blocks)
Cause DIRECT noncompetitive inhibition of reverse transcriptase by binding to its active center
ACTIVE as administered
SE: rash, hypersensitivity reactions, CNS effects, teratogenic
*see STEPS 3 & 4 of replication cycle
2. INSTIs (integrase strand transfer inhibitors)
Example. Raltegravir (Isentress)
MOA:
Prevents insertion of HIV-derived DNA into DNA of CD4 cellsblocks DNA replication (Integrase)
Active against HIV strains resistant to other drugs
SE: hypersensitivity reactions
*see STEP 5 of replication cycle
3. PIs (protease inhibitors)
Example. Darunavir
Most effective
MOA:
Bind to HIV protease and prevent enzyme from cleaving HIV polyproteins. Enzymes and structural proteins are left nonfunctional and cannot construct new virus.
Metabolized by cytochrome P450 enzymes
SE: hyperglycemia, fat redistribution, hyperlipidemia, bone loss, elevated LFTs, increased bleeding risk for hemophilia, inhibit P450
*see STEP 10 of replication cycle
4. Fusion inhibitors
Example. Enfuvirtide (Fuzeon, T-20)
MOA:
binds with gp41 on the viral envelopeblocking entry of HIV into CD4 T cells 181
Indicated for HIV resistant to other viruses
SE: universal injection-site reactions, inconvenient
*see STEP 2 of replication cycle
5. Chemokine Receptor 5 (CCR5) antagonists
Example. Maraviroc (Celsentri)
MOA:
blocks HIV entry into CD4 cells, limited to specific HIV strains
SE: cough, dizziness, rash, abdominal pain
*see STEP 1 of replication cycle
**Maraviroc and Enfuviritide (fusion inhibitors)
are the only antiretroviral drugs that
BLOCK HIV entry!!**
*Most patients take 2 NRTIs + INSTI, NNRTI or PI
Describe monitoring that should occur for patients on HAART
Plasma HIV RNA (viral load)*
Indicates magnitude of HIV replication
Predicts rate of CD4 T-cell destruction
HIGH: untreated pt, recent infection, lapse in adherence
GOAL: 20-75 copies/mL
CD4 T-cell counts (800-1200 cells/mm3)
Indicates how MUCH damage the immune system has already suffered
HIV Drug Resistance
2 resistance tests (assays)
$$$
Frequent false-negative results
HLA-B*5071 Screening
Tests for genetic variation (abacavir)
CCR5 Tropism
Tests for presence of CCR5 co-receptor
Some strains of HIV need to bind with CCR5 receptors to enter CD4 cells
Assay needed if going on Maraviroc (CCR5 antagonist)
Discuss prophylactic therapy
Prophylactic therapy is a preventive measure.
PrEP (pre-exposure): use of antiretroviral drugs to prevent HIV infection in an HIV-negative person
Indication:
Men who have sex with men (based on current studies)
Those at high risk of HIV acquisition
PEP (post-exposure):
Indication:
Accidental exposure (needle stick, splash with bodily fluids)
Start within 1-2 hours of exposure, take for 28 days
Who is at greatest risk for opportunistic infections
Any patient with a CD4 count < 200
Opportunistic Infections
An infection caused by a pathogen that takes advantage of a weakened immune system
Categorized by type:
Bacterial
Mycobacterium TB
Fungal
Pneumocystis pneumonia (PCP), Candidiasis (thrush), Cryptococcal Meningitis
Protozoa
Toxoplasmosis
Viruses
CMV retinitis, herpes simplex, zoster, HPV
Manifestations by System
Respiratory
Pneumonia, TB
GI
Diarrhea, gastroenteritis, esophagitis
Nervous System
Asymptomatic neurocognitive impairment, toxoplasmosis
Metabolic
Lipid disorders, diabetes
