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128 Cards in this Set
- Front
- Back
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define HIV
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Human Immunodeficiency Virus
retrovirus (RNA virus) - in order to infect human cells it must transcribe viral RNA into DNA via RT (reverse transcriptase enzyme) |
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define AIDS
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Acquired Immunodeficiency Syndrome
clinical diagnosis, end stage HIV-infection |
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describe the way HIV works
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-glycoproteins on the viral envelope bind to T-cell
-capsid injects contents of virus into T-cell, including HIV RNA, RT, protease, and integrase -RT converts viral RNA to DNA -integrase combines viral DNA into host DNA -HIV-host DNA is translated into protein -HIV protease cleaves translated protein to create mature HIV virion |
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once a host cell is infected, what are the two options
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1) the virus becomes latent and the infected cell continues to function
2) the virus becomes active and replicates, and a large number of virus particles that can then infect other cells are liberated |
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3 modes of HIV transmission
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-sexual contact
-exposure to body fluids -perinatal |
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HIV is NOT transmitted via
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-mosquitoes
-saliva -tears -sweat |
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Define Stage I HIV
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-lab HIV documentation AND
-CD4 count > 500 cells/microL OR -CD4 %age of >29 AND no AIDS defining condition |
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Define Stage II HIV
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-lab HIV documentation AND
-CD4 count 200-499 cells/microL OR -CD4 %age of 14-28 AND no AIDS defining condition |
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Define Stage III HIV
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-lab HIV documentation AND
-CD4 count <200 cells/microL OR -CD4 %age of <14 OR no AIDS defining condition |
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Define HIV with Stage Unknown
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-lab HIV documentation
but NO CD4 count or unknown AIDS defining condition status |
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8 Stages of HIV infection
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-viral transmission
-primary infection (acute retroviral syndrome) -seroconversion (development of antibodies, will not test positive until antibodies present in 6-12 weeks or up to 6 months) -asymptomatic chronic infection -symptomatic HIV infection -AIDS -Advanced HIV/AIDS with CD4 <50 cells/mL -Death |
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describe primary infection
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Acute Retroviral Syndrome
-Symptomatic in 80-90% of people -Occurs 2-4 weeks after exposure -Lasts 1-2 weeks -Very high viral loads - increased likelihood of transmission -not everyone will seek medical attention -diagnosis missed in up to 75% of patients |
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S/Sx of acute retroviral syndrome
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-fever
-fatigue -lymphadenopathy -pharyngitis -rash (erythematous maculopapular with lesions on face/trunk and sometimes palms or soles) -myalgia/arthralgia -NVD -HA -weight loss -thrush -neurologic Sx |
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gold standard for Dx of HIV/AIDS
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HIV-1 Antibody testing (ELISA) with confirmational Western Blot
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other antibody tests for diagnosing HIV
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blood
saliva urine rapid HIV tests - all require ELISA and Western Blot confirmation |
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2 markers of HIV disease progression
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CD4 lymphocyte count
HIV RNA |
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describe CD4 lymphocyte count
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reflects EXTENT of disease progression
-normal is 500-1500 cells/mL -CD4% may be more predictive because it's less variable |
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describe HIV RNA
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-serves as the marker for viral load
-correlates with RATE of disease progression -used to determine timing of ART PCR, bDNA |
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define viral set point
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equilibrium between viral replication rate and host immunity (6-12 months post infection)
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define resistance predilection
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-reverse transcriptase is highly error prone
-numerous variants of original HIV strain exist within patient -rapid selection of resistance subtypes can occur with therapy that doesn't adequately suppress viral replication |
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MoA of nucleoside reverse transcriptase inhibitors (NRTIs)
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-TP'ed via kinases to active form
-Compete with endogenous nucleoside TPs for incorporation into DNA strand -Terminate chain elongation |
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7 NRTIs
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zidovudine
didanosine (NO FOOD) stavudine lamivudine emtricitabine abacavir tenofovir |
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special thing about zidovudine
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1st HIV medication (1987)
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zidovudine's 2 dose limiting ADRs
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anemia, neutropenia
(compliance) |
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zidovudine's common ADRs
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HA, N, malaise (tolerance in 4-6 weeks)
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zidovudine's food requirement
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w/ or w/out
w/ can help reduce N |
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how are lamivudine and emtricitabine related
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emtricitabine is the 5'-fluorinated derivative of lamivudine
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formulations of lamivudine and emtricitabine
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tabs/caps
PO soln |
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ADRs for lamivudine and emtricitabine
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minimal
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food requirement for lamivudine and emtricitabine
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w/ or w/out
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ADRs of abacavir
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hypersensitivity
-3-5% of patients -occurs on day 10 -fever, HA, malaise, NV -rash in 50% over a few days -STOP esp if >2 Sx -Sx resolve in 2 days after stopping -DO NOT RECHALLENGE |
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food requirement for abacavir
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w/ or w/out
EtOH increases abacavir levels |
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screening requirement before use of abacavir
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HLA-B*5701 to prevent hypersensitivity reaction
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ADRs of didanosine
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pancreatitis
peripheral neuropathy (after months or years - gabapentin) N/D |
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food requirement for didanosine
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w/out food
didanosine is broken down by stomach acid |
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ADRs of stavudine
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pancreatitis
PN lipodystrophy HLD |
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food requirement for stavudine
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w/ or w/out meals
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ADRs for tenofovir
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GI: NVD flatulence
renal insufficiency asthenia HA |
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food requirement for tenofovir
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w/ or w/out food
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DI between tenofovir and atazanavir
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tenofovir lowers atazanavir levels
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Class ADRs for NRTIs
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MITOCHONDRIAL TOXICITY
neuromuscular -myopathy -cardiomyopathy hepatic CAN BE FATAL -lactic acidosis -hepatic steatosis GI - pancreatitis hematologic - pancytopenias metabolic - lipodystrophy |
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factors that affect toxicity
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-concentration dependent mitochondrial toxicity
-onset requires prolonged time -additive or s ynergistic effects |
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MoA of nonnucleoside reverse transcriptase inhibitors
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bind to the hydrophobic pocket near the active site of reverse transcriptase and block DNA polymerization
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4 NNRTIs
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efavirenz
nevirapine delavirdine etravirine |
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*ADRs of efavirenz
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CNS - abnormal dreams, somnolence, insomnia, abnormal thinking, worsening depression - usually decrease after 4-6 weeks of therapy
RASH TERATOGENIC |
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food requirements of efavirenz
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no food - food increases absorption and increases adverse effects
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ADRs of nevirapine
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HEPATITIS - F CD4 >250 and M CD4>400
weight risks and benefits |
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food requirement of nevirapine
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w/ or w/out food
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ADR of delavirdine
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HA
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food requirement of delavirdine
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w/ or w/out
requires acid environment DO NOT TAKE WITH ANTACIDS |
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ADR of etravirine
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severe skin rash (SJS)
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food requirement of etravirine
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with food
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special use of etravirine
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use when single point mutation K103N wipes out use of all other NNRTIs
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NNRTI Class ADE
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Rash - SJS
-usually self-limiting in 10-14 d, doesn't require d/c or Tx hepatoxicity - increases transaminase levels, can be transient or continuous (nevirapine - fatal hepatic necrosis) |
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MoA of protease inhibitors
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HIV protease is the enzyme responsible for cleaving polyproteins into essential functional proteins
PIs are HIV specific and affect assembly and release so new virions are immature and unable to infect new cels |
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10 PIs
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atazanavir (FOOD)
amprenavir fosamprenavir saquinavir lopinavir ritonavir (FOOD) indinavir (NO FOOD) nelfinavir (NO FOOD) tipranavir darunavir (FOOD) |
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ritonavir dosage formulations
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caps (REFRIGERATED, or RT x 30 d)
oral soln |
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why is ritonavir used as a booster?
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potent inhibitor of 3A4, allowing for increased levels of other PIs without increasing dose
never used alone due to tolerance issues |
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ADRs of ritonavir
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GI intolerance
paresthesias hepatitis (massive lipodystrophy) |
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ADRs for amprenavir and fosamprenavir
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rash
GI intolerance (f-APV << APV) HA |
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food requirement for amprenavir and fosamprenavir
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w/ or w/out food
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ADRs of indinavir
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**nephrolithiasis
hyperbilirubinemia (adherance) GI intolerance HA blurred vision dizziness |
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food requirement of indinavir
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no food (1 hour before or 2 hours after meals if unboosted)
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ADRs of saquinavir
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GI (ND)
HA |
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food requirement of saquinavir
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w/ or w/out food
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ADR of nelfinavir
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D
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food requirement for nelfinavir
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w/ food
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ADR of lopinavir/ritonavir
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NVD
asthenia (weakness) |
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food requirement for lopinavir/ritonavir
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w/ or w/out food
take soln w/ food |
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ADRs of tipranavir
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hepatotoxicity
rash (sulfa) |
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food requirement for tipranavir
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w/ or w/out
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ADRs of atazanavir
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hyperbilirubinemia (adherance)
prolonged PR interval (1st deg AV block) (no HLD) |
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food requirement for atazanavir
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w/ food
requires acid environment for absorption avoid antacids and PPIs |
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ADRs of darunavir
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GI
HA rash (sulfa) |
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food requirement for darunavir
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take with food
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Class ADRs for PIs
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-GI intolerance
-HLD (but not atazanavir) -HTG (esp w/ ritonavir) -hyperglycemia -fat maldistribution -possible increase in bleeding with hemophilia -tansaminase elevations |
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fusion inhibitor MoA
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prevents fusion of HIV viral envelope with host cell
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1 fusion inhibitor
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enfuvirtide
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ADR of enfuvirtide
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-increased rate of bacterial pneumonia
-hypersensitivity rxn (rare) - rash, fever, N, chills, hypotxn, do not rechallenge -injection site reaction (itchy or bruisy nodules or cysts) |
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MoA of CCR5 antagonists
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only useful in pts who have CCR5 co-receptor (v. CXCRX co-R)
blocks binding of CCRF co-receptor to viral envelope when attempting to bind to host cell |
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ADRs of maraviroc
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abdominal pain
cough URTI hepatotoxicity |
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food requirement for maraviroc
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w/ or w/out food
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MoA of integrase inhibitors
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inhibits activity of HIV integrase which prevents integration of viral DNA with host DNA
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1 integrase inhibitor
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raltegravir
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ADR of raltegravir
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ND
HA pyrexia CPK elevation |
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food requirement of raltegravir
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w/ or w/out
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6 renal adjustment HIV meds
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NRTIs
except abacavir zidovudine lamivudine emtricitabine didanosine stavudine tenofovir |
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2 classes of HIV meds with GI ADR
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NRTIs
PIs |
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2 HIV meds with pancreatitis, PN ADRs
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didanosine
stavudine |
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6 HIV meds that must be taken with food
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etravirine
ritonavir azatanavir darunavir nelfinavir lopinavir/ritonavir soln |
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3 HIV meds that must be taken without food
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didanosine
efavirenz indinavir |
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6 indications for initiating HAART
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• Hx of AIDS defining illness
• CD4 count <350 cells/mL • CD4 count 350-500 cell/mL • Pregnant women • Persons with HIV-ass’d nephropathy • Persons co-infected with HBV |
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4 benefits of HAART
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-maintenance of a higher CD4 count and Px of potentially irreversible damage to the immune system
-decreased risk for HIV-ass'd complications that can occur with CD4 > 350 cells/mL -decreased risk of non-opportunistic conditions (CV, renal, liver, malignancies, infxns) -decreased risk of HIV transmission to others |
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6 risks of HAART
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-development of Tx-related ADRs/toxicities
-development of drug resistance bc of incomplete viral suppression, resulting in loss of future treatment options -less time for the patient to learn about HIV and its treatment and less time to prepare for the need for adherence to therapy -increased total time on medication, with greater chance of Tx fatigue -premature use of therapy before the development of more effective, less toxic, and/or better studied combinations of antiretroviral drugs -transmission of drug-resistant virus in patients who do not maintain full virologic suppression |
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6 goals of HAART
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• Reduce HIV-related M/M
• Reduction in HIV-ass’d inflammation and it’s ass’d complications • Improve quality of life • Restore and preserve immunologic function • Maximally and durably suppress viral load • Prevent vertical HIV transmission |
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3 strategies to achieve treatment goals
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-selection of initial combination regimen
-pretreatment drug resistance testing -improving adherence |
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3 preferred options for HAART
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NNRTI + 2NRTI
PI (w/ r booster) + 2NRTI INSTI + 2NRTI |
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what is the preferred NNRTI based HAART?
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efavirenz (NNRTI)
tenofovir emtracitabine or lamivudine -AVOID WITH PREGNANCY POTENTIAL -AVOID IN PTSD/PSYCH DISORDERS |
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what is the preferred PI based HAART regimen?
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atazanavir/ritonavir OR
darunavir/ritonavir (QD) tenofovir emtricitabine |
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what is the preferred INSTI-based HAART regimen?
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raltegravir
tenofovir emtricitabine |
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what is an option when NRTI options are limited? (can't have 2)
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PI
NNRTI NRTI |
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when is enfurvitide used?
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this fusion inhibitor is reserved for patients with extensive drug resistance and is combined with traditional HAART
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2 advantages of NNRTI therapy
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-less dyslipidemia and fat maldistribution than in PI regimens
-long half-lives (QD dosing) |
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4 disadvantages of NNRTI therapy
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-single mutation resistance (K103N)
-cross-resistance -CYP450 DIs -transmitted resistance common |
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2 advantages of PI therapy
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-longest prospective data
-higher genetic barrier to resistance (4-5 mutations required) |
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2 disadvantages of PI therapy
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-metabolic complications
-greater potential for CYP450 DIs (esp ritonavir) |
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5 benefits of deferred HAART therapy
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-avoid negative effects on quality of life
-avoid drug-related toxicity -preserve future drug options -delay development of drug resistance -decrease total time on medications |
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3 risks of deferred HAART therapy
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-possibly irreversible immune system depletion
-increased possibility of progression to AIDS (CD4 <200) -possible increased risk of HIV transmission |
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what is required before starting or changing therapy?
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2 CD4 counts
2 HIV viral loads on 2 separate occasions (genotypic assays require a certain viral load to be valid) |
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monitoring for HAART therapy
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check HIV RNA level
--1 month after therapy is initiated or changed -Q month until goal is reached (undetectable) -every 2-4 months thereafter |
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viral loads should become undetectable within
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24-36 weeks of initiating therapy
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failure to achieve an undetectable viral load by 16-24 weeks indicates
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poor adherence
inadequate drug absorption drug resistance |
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2 things that can cause increases in viral load
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immunization or illness
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-considerations for changing ARV regimens
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-suboptimal reduction of HIV RNA
-reappearance of HIV RNA after suppression -declining CD4 count -intolerance to ADRs/tox |
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when changing therapy, if the reason fro failure is toxicity from, intolerance to, or adherence difficult with one of the ARTs in regimen, then...
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substitute another drug in place of the offending drug
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when changing therapy, if the reason for failure is virologic, then...
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change the ENTIRE REGIMEN
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K103N resistance means
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high level resistance to all current NNRTIs
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M184V resistance means
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high level resistance to lamivudine and emtricitabine
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TAMS/NAMS resistance means
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cross-resistance to all NRTIs
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lab evaluation of the HIV patient
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CBC with diff
CD4 count HIV RNA PCR (viral load) renal/liver function tests (chem 12) RPR (syphilis) toxoplasma IgG Hepatitis B PPD, CXR at baseline |
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drug-drug interactions to be concerned about in HIV pts
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P450 moderated drugs
absorption Rx medications (1 Rx location) OTC/herbals other ARTs |
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P450 meds to avoid in HIV patients
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midazolam, triazolam
ergot derviatives lova/simvastatin anticonvulsants rifampin corticosteroids St. John's Wort |
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P450 meds to monitor/adjust in HIV patienst
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oral coontraceptives
methadone PDE5 inhibitors rifabutin |
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drugs that affect absorption of HAART
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acid reducing agents
-PPIs CI-ed with atazanavir -H2RAs and atazanavir - use only boosted atazanavir and split dosing if possible binding agents -bile acid sequestrants -charcoal |
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efavirenz is a P450 ___
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inducer
use PIs only if boosted |
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tenofovir interacts with which other 2 ARTs
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atazanavir/ritonavir - only use boosted, due to decreased levels
didanosine - decrease didanosine dose to 250 mg QD |
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optimal suppression of viral load requires __% adherance
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90-95%
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9 ways to improve adherence
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-establish readiness to start therapy
-provide education on medication dosing -review potential ADRs -anticipate and Tx ADRs -utilize education aids -simply regimens, dosing, food requirements -engage family, friends -utilize team approach with nurses, pharmacists and peer counselors -provide accessible, trusting health care team |
