Antivirals Flashcards
how viruses work?
- Attach
- enter
- uncoat
- synth proteins
- synth nucleic acids
- package and assembly
- viral release
Basic concepts
- viruses are intracellular
- depend on host machinery
antivirals do 3 things: only on active replicators
1. block entry into cell
2. block exit from cell
3. interfere with virus specific proteins once translated in cytosol
DO NOT HAVE ANY EFFECT ON VIRUSES IN LATENT STATE
agents specific to certain viruses or viral classes
Viruses currently tx
- Herpes
- Hepatitis B&C
- HPV
- influenza A&B
- RSV
- HIV
Herpes virus
DNA enveloped virus
six types:
1. herpes simplex virus 1
2. herpes simplex virus 2
3. varicella-zoster virus
4. cytomegalovirus
5. epstein barr virus
6. human herpes virus 8- HIV
Herpes antivirals:
anti hsv and vzv
* Valacyclovir
* penciclovir
* acyclovir
* famciclovir
* trifluridine
anti-cmv
* Ganciclovir
* Valganciclovir
* Foscarnet
* Cidofovir
interact with protein synth
Acyclovir
zovirax
synthetic quanosine analogue which leads to terminaiton of viral replication
Activity: HSV1, HSV2, VZV
low bioavailability
can take with food but give frequently bc of short half life=5x daily=low pt compliance
renal adjustment
monitor pts on zidocudine (hiv meds) and acyclovir-> increase somnolence and lethargy
Acyclovir activation and Clinical uses
activation: must have active infection-> viral thymidine kinase requried-> leads to chain termination by competing in dna polymerase
Uses:
* primary genital herpes
* secondary tx for genital herpes
* suppression therapy
* primary oral herpes
* shingles
white plaques w/ erythematous base, herpetic gingiiostomatatis
IV- serious
Topical-initial type 2 infection- not curative but may help with symptoms->prevention of recurrence during pregnancy @ 36 wks gestation
IV acyclovir clinical uses
almost only one thats IV
- herpes simplex encephalitis
- neonatal hsv infxn
- serious hsv or vzv in immunocomp host
Caution:
reversible renal toxicity
neurologic effects-> seizures
need adequate hydration
other anti hsv agents
Valacyclovir- more bioavail, SE: NVRash, suppressive therapy in pregnant woman
Famciclovir- good bioavail and expensive
Penciclovir cream- only topically
Trifluridine- used topically by opthalmologists
TX of varicella or cutaneous zoster
get picture
Tx decreases:
* total # of lesions
* duration of sxs
* viral shedding
* risk of post herpetic neuralgia
w/in 24 hours of rash (varicella-chkn pox) onset or 72 for cutaneous zoster
Cytomegalovirus
common virus infects all age groups
infants and HIV- vulnerable
over half of adults by age 40 have been infected- w/out sxs
Congenital cmv- 1 out of 200 born with it
* 15% develop progressive hearing loss
Transmission: person to person-> kissing, intimate contact, vertical transmission-mother child, blood transfusions, stem cell transplantation
Anti CMV AGENTS
-
Ganciclovir- older used IV for CMV- also for CMV volitis, esophagitis, pneumonitis
* SE: myelosuppresion and peripheral nueropahty - Valganciclovir- great oral bioavail- prophyl for transplant or AIDS pt
- Foscarnet- poor bioavail- used for cmv and acyclovir resistant HSV
* electrolyte abnormalities, renal impairment - Cidofovir- IV for CMV retinitis
* renal impairment, uveitis
Anogenital warts
Condyloma acuminatam
caused by HPV types 6 or 11, 16 or 18 are occasional
Goal: remove wart and ameliorate sxs
patient applied tx:
1.Imiquimod cream-> stim interferon
2.Sinecatechins-> upreg apop genes
Provider administration:
1. Cryotherapy with liquid nitrogen
2. Surgical removal
Hepatitis A
Vaccine preventable liver infxn
* stool and blood of infected
* very contagious by fecal/oral or person to person
* SXS: fatigue, nausea, vomiting, anorexia, stomach pain, then jaundice
* Not usually long lasting over a few months and self limiting
VACCINE VACCINE VACCINE- Hepatitis A virus ag 25 units/0.5 ml, inactivated
Ig vacc= for short term prevention
Hepatitis B
DNA virus infects hepatocytes
DX of acute HBV infxn= HBsAG and antiHBc
DX of chronic HBV= persistence of HBsAG for greater than 6 months
Goal of therapy: NOT CURABLE, suppress hbv replication to prevent progression to CIRRHOSIS AND HEPATOCELLULAR CARCINOMA or prevent reactivaiton
Cirrhosis
Hepatocellular injury-> fibrosis and regenerative nodules
Causes: Chronic viral hep, alcohol, drug toxicity, non alcoholic fatty liver disease
End stage chronic liver disease
SXS: ascites, jaundice, variceal hemorrhage, hepatic encephalopathy- altered mental status
Hepatocellular carcinoma
another progressionof Hep B
When should we treate Hepatitis B?
Active HBV + altered liver function +/- cirrhosis
Pharmacologic therapy for Hep B
1.immune mediating-Pegylated interferon alpha
2.Antiviral agents- BBW for lactic acidosis= preferred agents due to barrier of resistance
* entecavir, tenofovir, diprovoxil
Original therapy for HBV
Interferons- Peginterferon alfa
compensated disease- favorable liver biopsy to show compensated
SE: flu like sx (give nsaid), bone marrow suppression, anxiety/depression, thyroid, autoimmune
Pegylated interferons: increase half life
Vaccination of Hep B
Most EFFECTIVE STRATEGY
requires multiple doses for improved response
3 single ag products:
1. Recombivax
2. Engerix b
3. Heplisav-b
combination vaccine:
1.twinrix- A and B
2.Pediarix- dtap and hbv- kids
3.Vaxelis: HPV, DTap, IPV
Heplisav b vaccine- novel adjuvant for immunogenicity
whom should be given and why should you DEFINITELY get the vacc
- Hep BV- to all household and sexual contacts who are not known to be immune
- likelihood of progression to chronic HBV infection <5%
- loss of IgG>10 yrs post vaccine but memory still up to 30 yrs past
Hepatitis C
Goal: eradicate virus
Testing: Recent infxn may not have AB so still RNA test
test AB-> RNA-> acute or past
Acute: hcv is a single stranded RNA virus lacking a proofreading polymerase
Clearance w/out therapy= 25-30%
new guidelines= tx immediately to decrease transmission of HCV
TX regimens are same as chronic hep
Direct actign antiviral Agents
HCV
Targets 1 of 3 on hcv virion-> MUST BE IN COMBO WITH ATLEAST 2 DRUGS ACTING ON OTHER TARGETS
Drug drug interactions in general: Carbamazepine, phenobarbital, phenytoin, oxcarbazepine, rifampin, st. john’s wort
Hepatitis C classes of direct acting antiviral agents
may be combo to eradicate
- Nonstructural protein (NS)5A inhibitors- Pibrentasvir and Velpatasvir
- NS5B nucleoside polymerase inhibitors- Sofosbuvir
- NS5B nonnucleoside polymerase inhibitors- Glecaprevir
- NS3/4A protease inhibitors
Nonstructural proetin (NS) 5A inhibitors
NS5A protein assists in both viral replication and assembly of HCV-> exact MOA is unclear
1. Pibrentasvir- avail only with Glecaprevir, NOT REC IN HEPATIC IMPAIRED, excreted: biliary
2. Velpatasvir- fixed with Sofosbuvir- no dose adjustment for renal or hepatic- requires acidic environ for absorption
NS5B RNA polymerase inhibitors
NS5B is an RNA dependent RNA polymerase in post translational processing in rep of HCV
1. Sofosbuvir
* nucleoside analogs target catalytic site- RARE CASES OF SYMP BRADYCARDIA W/ AMIODARONE
NS3/4A protease inhibitors
inhibits the NS3/4A serine protease necessary for the proteolytic cleavage of HCV encoded polyprotein
1. Glecaprevir:
* combo with Pibrentasvir
Who is not eligible for simplified tx
- current or prior episode of decompensated cirrhosis
- prior hep c tx
- end stage renal disease
- HIV or HBsAG positive
- Current pregnancy
- known or suspected hepatocellular carcinoma
- prior liver transplant
bc of hepativ impairment
ALL HIGHLIGHTED
Child- Pugh score
predict mortality in cirrhosis
Portal decompression sxs-> see if candidate
Bilirubin
albumin
INR
Ascites
Encephalopathy
Chronic Hepatitis C
tx for naive adults w/ cirrhosis
- Mavyret= Glecaprevir/pibrentasvir= 1-6 genotypes
- Epclusa= Sofosvubir/Velpatasvir= 1,2,4,5, or 6
Mavyret drug interactions
glecaprevir/pibrentasvir
inhibit P-glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptide
* coadmin with drugs that are substrates of above= INCREASE PLASMA CONC
* coadmin drugs that inhibit hepatic of above= increase plasma conc of Glecaprevir or pibrentasvir
Carbamazepine, efavirenz, and St. john’s wort= significant decrease plasma conc
Epclusa regimen
velpatasvir/sofosbuvir
AE: headache, fatigue, nausea, asthenia, insomnia
St. John’s wort increases interactions w/ meds
Ribavirin
Decomp cirrhosis
Decompensated cirrhosis or patients with HC GT3
MOA not well understood
AE: Hemolytic anemia- complaints of fatigue
pregnancy category X= 2 forms of contraception during tx and for 6 months after
Testing prior to tx of Hep C
- Hepatitis B infection- HBV reactivation reported during tx-> fulminant hepatitis, hepatic failure, death
- Quantitative HCV testing-> to confirm chronic infxn and monitor response to therapy
- HCV genotyping- affect tx choice and need for pretx resistance testing
- HIV ag/ab test
- asses of underlying liver disease- guide tx options
- General labs w/in 3 mo of starting: CBC, INR, HEPATIC FUNCTION PANEL, eGFR
Influenza
sialic acid is key-> removes acid off sugar chains-> modify host respons
then contagious
type A-> devided into subtypes of Hemagglutinin H and Neuraminidase N on surface
B
C
Influenza FDA approved tx
- Oseltamivir phosphate- Tamiflu= neuraminidase inhibitor
- Zanamivir- Relenza= Neuraminidase inhibitor= inhaled
- Peramivir- Rapivab= Neuraminidase inhibitor- in hospital
- Baloxavir Marboxil- Xofluza
MOA of tamiflu= doesnt allow exit
Oseltamivir- tamiflu
Sialic acid analog interferes with viral release which aborts infxn
USE FOR A AND B
ideally given within 48 hours
Seasonal H1n1 develop resistance quickly
Children: cdc tec tx from birth
american acad of pediatrics - rec 2 wks and older
Prego safe
Hospitals use
SE: NV Headaches
Zanamivir- Relenza
inhalation powder- not widely used
seasonal h1n15 remain sensitive- dont use if people have breathing issues
SE: bronchospasm, sinusitis, dizziness
Peramivir- Rapivab
IV single dose
SXS allev 21 hrs sooner, Fever resolved 12 hours sooner
SE: diarrhea
Baloxavir marboxil- Xofluza
endonuclease inhibitor
MOA: prevents RNA cutting enzyme from hijacking host mRNA transcription process
for uncomplicated flu
pt 12 and older
sick <48 hrs
potential for rapid development of resistance
Respiratory syncytial virus infection
RSV
who is at risk?- premature infants, younger than 6 mo, children suppressed, kids with neuromuscular disorders bc cant cough
Prophylax for infants and kids:
Palivizumab- Synagis-> monthly IM injxn during season
FALL, WINTER, SPRING
Coronavirus (Covid 19)
Severe acute resp syndrome- coronavirus
Paxlovid- dont use severe renal impairment or hepatic
Veklury-dont use severe renal impairment
Lagevrio- if prego
Outpatient:
Veklury
National institute of health recommendations for nonhospitalized pts
Dexamethasone or other syst corticosteroids for symptomatic tx
NIH rec for hospitalized adults
Symptomatic + Paxlovid and Remdesivir
Nirmatrelvir-Ritonavir (Paxlovid)
combo of oral protease inhib
nirmatrelvir-blocks activity of sars cov protease-> enzyme req for viral rep
ritonavir-> slows metab of nirmatrelvir to remain active for longer
DOSE DEPENDENT ON KINDY FUNCTION
Remdesivir (Veklury)
RNA polymerase inhibitor
approved emergency IV use in US in hospitalized pt infected with SEVERE DISEASE
AE: n, renal tox, diarrha, rash
study guide
- name viruses and antiviral tx
- clinical use of acyclovir and SE and interactions
- MOA of acyc and why not effective on others
- tx of CMV
- drug classes in Hep B and SE and monitoring
- classes of Hep c and SE and monitoring
- Influenza and MOA and why 1 drug is preferred
