Lecture 3 - Antiviral Agent 2 Flashcards
Hep A
RNA virus
Transmission: Fecal oral, sexual
Risks: Endemic travel, MSM, daycare
Hep B
DNA virus
transmission: Parenteral, sexual, vertical
Risks: MSMS, IV drug user, Liver transplant, HC worker,
Hep C
RNA virus, most problematic
Transmission: Parenteral, sexual vertical
Which Hep can cause liver damage?
Hep B and C
Hep A goes away
Hep A treatment
Self limiting, symptomatic treatment
Prevention = hepA vaccine
Hep B treatment
Can be chronic, use chronic antiviral
Prevention = HepB vaccine
Tenofovir & Entecavir have….
rapid activity, relatively safety, clinical experience
Lamivudine is…
relatively safe but more resistance
IFN-alfa isn’t really used due to….
unacceptable safety profile
Adefovir isn’t used much due to…
more resistance and nephrotoxicity
Drugs with low resistance barrier
Lamivudine, Emtricitabine
Drugs with low potency
Adefovir
Lamivudine (A.K.A 3TC) MOA
inhibits HBV DNA polymerase
Lamivudine DI
None clinically significant
Lamivudine Dose adjustment
renal dose/interval adjustment required
Lamivudine ADRs
Headache, fatigue, anemia, nausea
Mitochondrial toxicity**
Lactic acidosis**
Pancreatitis**
Adefovir MOA
inhibits HBV DNA polymerase
Adefovir ADRS
Nephrotoxicity
Decreased carotene lvls
Adefovir Dose adjustment
Renal dose/interval adjustment required
Adefovir DI
no sig interactions
Entecavir (MOA)
guanosine analog, inhibits HBV DNA polymerase
Entecavir ADRs
lactic aidosis
nausea
headache
dizziness
Entecavir DI
No sig interactions
Entecavir Dose adjustment
Renal dose/interval adjustment required
Emtricitabine FTC MOA
inhibits HBV DNA polymerase
Emtricitabine ADRs
hyperpigmentation of palms & soles**
lactic acidosis
headache
dizziness
Emtricitabine DI
no sig interactions
Emtricitabine Dosage adjustments
renal dose/interval adjustment req
tenofovir MOA
inhibit HBV DNA polymerase
Tenofovir ADRs
Osteoporosis
asthenia
renal toxicity
Tenofovir DI
PGP inhibitors / inducers
Tenofovir dosage adjustment
renal dose/interval adjustment required
more for TDF than TAF
TDF and TAF Tenofovir
TDF = Viread = 300mg QD TAF = Vemlidy = 25 mg QD
TAF doesn’t need dose adjustment when….
CrCl > 15 mL/min
Interferon Alfa 2a (Pegasus) MOA
Stimulates HLA Class I protein (immune enhancer)
longest 1/2 life
Interferon Alfa ADR
flue like lose hair CNS = depression, confused, sucidial Hematolgic Endocrine
Interferon Alfa dose adjustment
No recommended Renal insufficiency CrCl < 50ml/min
Interferon Alfa DI
Theophylline = inc Theo conc Zidovudine = inc myelosuppression
Mutation that will knock out lamivudine is…
YMDD mutation single point
What to do w/ LAM resistance?
Switch to TDF or TAF
What to do w/ ETV resistance
Switch to TDF or TAF
What to do w/ TDF+TAF resistance
Lam naive: Switch to ETV
LAM-R = Add ETV
What to do if MDR HBV?
Switch to ETV + (TDF or TAF) combo
Peginterferon alfa will work against which genotypes for HepC?
All of them
Interferon alfa dose is adjusted based on…
Hemoglobin and hematocrit
also careful with depression
ESRD req adjustment
Ribavirin MOA
- enhances immune clearance
- inhibition of IMPDH
- Inhibition of HCV RdRp
- RNA mutagenesis
used in combo
Which genotypes can Ribavirin be used for?
all of them
Ribavirin DI
azathioprine increases cytopenias
Abacavir, zidovudine = lactic acidosis
Ribavirin dose adjustment
req renal adjustment
also adjust for cell count, if dec then dec dose
Ribavirin ADR
Shit load of side effects
dont use men/women childbearing age
Where do Protease inhibitors work?
NS3
Protease inhibitors
Grazoprevir = GZR Voxilaprevir = VOX Glecaprevir = GLE
Where do Replication Complex inhibitors work
NS5A
Replication Complex Inhibitors
Elbasvir = EBR Ledipasvir = LDV Ombitasvir = OBV Velpatasvir = VEL Pibrentasvir = PIB
Where do NUC inhibitors work?
NS5B (Polymerase)
NUC inhibitors
Sofosbuvir = SOF
Where do Non-NUC inhibitors work?
NS5B (Polymerase)
Non-NUC inhibitors
Dasabuvir = DSV
-evir Drug Dose adjustments?
No dose adjustment
Elbasvir DI & Dose adjustment
No dose adjustment
DI = 3A4 Substrate
Ledipasvir DI & Dose adjustment
Amiodarone***, Antacids, H2 blockers, PPI
Dont use for CrCl < 30
Sofusbuvir DI & Dose adjustment
Use caution with CrCl < 30 ml/min*****
Avoid Amiodarone + strong PGP inducers
Drugs active against all genotypes HepC
Sofosbuvir-Velpatasvir-Voxilaprevir (Vosevi)
Sofosbuvir-Velpatasvir (Epclusa)
Glecaprevir/Pibrentasvir (Mavyret)
Recommended drugs to avoid for severe liver dysfunction
GZR/EBV
IFN
-evir are substrates of….
3A4
Dependent on transport protein metabolism too
potential inhibit and interact with plenty of other drug classes
-asvir interactions with….
3A4, transport proteins for metabolism too
Ledipasvir doesn’t req 3A4 adjustment but others do
Drugs that you dont want to give with doses of > 20mg of PPI
LDV/SOF
Ledipasvir/Sofosbuvir
Drugs that you dont want to give with PPI at all
SOF/VEL
Sofosbuvir/velpatasvir
NRTIs MOA
- inhibit HIV RNA dependent DNA polymerase, inhibit viral replication
- Incorporate into growing viral DNA chain-chain terminator
Shared NRTI’s side effects?
General: N,V,D
Mitochondiral toxicity
Hypersensitivity = abacavir**
Renal failure = tenofovir**
Hyperpigmentation = emtricitabine**
Anemia = Zidovudine***
NRTI Mitochondrial toxicity MOA
inhibition of mitochondrial DNA polymerase, impaired synthesis of mitchondrial enzymes, impaired ATP production
~50% mortality in most severe cases
Early signs for NRTI Mitochondrial toxicity
N, abdominal pain, weight loss/tachycardia, hyperventilation, weakness
Highest risk groups for NRTI Mitochondrial Toxicity
Combo of….
DDI + D4T
DDI + hydroxyurea
Prolonged duration of therapy
Females
Obese
Pregnant patients
NRTIs effect on Lipids…
increase in Cholesterol potentially
Older more effect than newer ones
Facial and extremity wasting with or without central adiposity associated with….
Stavudine
Didanosine
Zidovudine
Also older age, higher TG at start of therapy, CD4 nadir < 200
Changing d4T to TDF can cause….
reversal in lipids and limb fats
Abacavir info
AKA ABC
Early, w/I 6wks (Hypersensitivity syndrome (5-8%), fever,rsh, N,V,D)
Late ( CVD)
Before pts on Abacavir, do a test for….
HLA-B*5701, correlates with susceptibility to hypersensitivity
Dont give if positive
Do not rechallenge
Advantages of ABC
- coformulated with INSTI in 1st line regimen = Triumeq
- Long hx of use
- Not really cleared
Disadvantages of ABC
- Hypersensitivity
2. CVD
TAF is….
Alafenamide
TDF is….
Disoproxil Fumarate
Tenofovir ADE
Nephrotoxicity-AKI and Fanconi Syndrome
Osteopenia
Benefits of TAF > TDF
- less impact on BMD
- Less impact on markers of renal tubular dysfunction
- Low dose allows small tab coformulations
Benefits of TDF > TAF
- used for longer
- multiple coformulations
- TAF has weight gain
- recommended in pregnancy
- available as generic with 3TC
NRTI that are really eliminated and dosed except….
Abacavir
NNRTI specific mutation
K103N
NRTI specific mutations
M184V = most common, Lamivudine + Emtricitabine resistance, increased activity to Tenofovir and ZDV
K65R = resistance to most except ZDV
Abacavir DI
excessive Alcohol
Methadone
Didanosine DI
Allopurinol, consider reducing didanosine by 50%
Cidofovir
Stavudine DI
Zidovudine = Dont co admin
Tenofovir DI
Atazanavir = 300mg Atazanavir w/ 100mg ritonavir (booster) when used with tenofovir
Didanosine = reduce didanosine to 250mg QD