Antiviral Questions Flashcards
1
Q
What is the term for the outmost layer that covers most viruses?
A
Viral envelope, composed of elements of the host
- cell membrane
- endoplasmic reticulum
- or nuclear envelope
2
Q
What does the viral envelope cover?
A
Capsid
-shell composed of identical building blocks of capsomeres
3
Q
What does the capsid protect?
A
Viral nucleic acid
-either DNA or RNA
–single or double stranded
4
Q
Why do many viruses contain enzymes?
A
To catalyze reactions that
-lead to their replication
or
-cell entry
5
Q
Can viruses self replicate?
A
No
- cannot synthesize their own components to replicate
- dependent on host cellular processes for all synthetic functions
6
Q
What are virions?
A
Individual complete particles of virus
7
Q
How do retroviruses work?
A
RNA genetic material translated into DNA via reverse transcriptase
- then integrates into the host genome
- then transcription into mRNA
- then translation into protein
- then viral enzymes assemble the pieces of the puzzle into complete virions
- then released from the cell
8
Q
For viral infections, are patient specific susceptibility results available?
A
Rarely
- therapies chosen based upon general patterns of susceptibility for that type of virus
- HIV is the exception
9
Q
Can viruses be cultured?
A
Yes, but:
-many viral illnesses diagnosed through genetic testing for viral antigens or nucleic acids
10
Q
How are viral infection followed to see if they improve?
A
Usually symptoms followed
-tests are not usually followed quantitatively
11
Q
Which agents are primarily used against herpes simplex virus (HSV) and varicella-zoster virus (VSV)?
A
- acyclovir
- valacyclovir
- famciclovir
12
Q
How is acyclovir’s absorption orally?
A
Poor
-must be given up to five times daily
13
Q
Which HSV/VZV agent is the only one available in an IV form?
A
Acyclovir
14
Q
What are valacyclovir and famciclovir?
A
Pro-drugs
- absorbed better
- can be administered less frequently
15
Q
What is the agent of choice for serious HSV infections (ex: encephalitis)?
A
Acyclovir
16
Q
What is the MOA of anti-HSV/VZV agents?
A
Nucleoside analogs that (after phosphorylation) are incorporated into the elongating viral DNA strand just like cellular nucleotides
- lack the functional group that allows the next nucleotide to be added
- halts replication
17
Q
What organisms do anti-HSV/VZV agents have GOOD activity against?
A
- HSV-1
- HSV-2
18
Q
What organisms do anti-HSV/VZV agents have MODERATE activity against?
A
-VZV
19
Q
What organisms do anti-HSV/VZV agents have POOR activity against?
A
- Epstein-Barr virus (EBV)
- cytomegalovirus (CMV)
- HIV
20
Q
How are anti-HSV/VZV agents tolerated?
A
Generally well tolerated with few adverse effects
21
Q
What is the most concerning adverse effect of anti-HSV/VZV agents?
A
Nephrotoxicity
-through either crystallization
or
-acute interstitial nephritis (AIN)
-most commonly associated with higher doses of IV acyclovir
22
Q
How can acyclovir crystallization be prevented?
A
- hydration
- correct dosing in renally impaired patients
23
Q
What are some CNS effects that can occur with anti-HSV/VZV agents?
A
- seizures
- tremors
- other CNS effects
24
Q
What are the more common adverse effects associated with anti-HSV/VZV agents?
A
- nausea
- diarrhea
- rash
25
What adverse effect has been reported with valacyclovir in HIV patients?
Thrombotic thrombocytopenic purpura
26
What is valacyclovir?
Pro-drug of acyclovir
- substantially improved bioavailability
- less frequent dosing
- higher cost
27
What is famciclovir?
Pro-drug of penciclovir
-penciclovir only available as a topical preparation
28
Describe acyclovir dosing.
Varies widely by:
- indication
- host status
29
When is acyclovir most toxic?
When given in combination with:
-diuretics
or
-other nephrotoxins
-keep patients hydrated during therapy (especially if given in higher IV doses)
30
What is the acyclovir the drug of choice for?
Severe or difficult to treat HSV infections; ex:
- encephalitis
- severe HSV outbreaks among HIV patients
31
What can infections can any anti-HSV/VZV agent be used to treat?
HSV-2 infections (genital herpes)
-to prevent outbreaks
or
-decrease symptom duration
Effective in treating VZV infection
32
What is one thing to consider when prescribing anti-HSV/VZV agents?
Cost
-oral acyclovir is less convenient but much less expensive
33
What are the anti-cytomegalovirus (CMV) agents?
- Gangciclovir
- Valgangciclovir
- foscarnet
- cidofovir
34
Describe CMV.
- causes infections that are usually asymptomatic in immunocompetent patients but devastating in immunocompromised patients
- ~60% of Americans become seropositive for CMV by adulthood; infection is lifelong
35
How do anti-CMV agents work?
Prevent viral replication
36
What is the MOA of val/gangciclovir?
Nucleoside analogue
- after phosphorylation, integrates into viral DNA by DNA polymerase
- halts viral replication
37
What is the MOA of cidofovir?
Nucleotide analogue
-similar MOA to gangciclovir
38
What is the MOA of foscarnet?
Pyrophosphate analogue
-acts as a noncompetetive inhibitor of the DNA and RNA polymerase of multiple viruses
39
What organisms do anti-CMV agents have GOOD activity against?
- CMV
- HSV-1
- HSV-2
- VZV
- EBV
40
What organisms do anti-CMV agents have POOR activity against?
-HIV
41
What are adverse effects that can occur from any anti-CMV agent?
- nausea
- vomiting
- diarrhea
42
What are the adverse effects of val/gangciclovir?
Myelosuppression
- dose dependent
- relatively common
- particularly when used in higher doses or in renally impaired patients without dose adjustment
43
What are adverse effects of foscarnet?
- nephrotoxic
- neurotoxic
- penile ulcers
- reserved for patients who have failed other therapy
44
What adverse effect dose cidofovir cause?
Exhibits nephrotoxicity
-uncommonly used drug
45
What drug has replaced oral gangciclovir?
Valgangciclovir
-has much better bioavailability
46
What are some considerations when dosing gangciclovir?
- patient weight
| - renal function
47
What does the package insert of valgangciclovir specify for dose adjustments?
Adjustments based on renal function but not weight
-dose reduction should be considered in underweight patients (especially if at high risk of toxicity)
48
What strengths is valgangciclovir available in?
- 900mg
| - 450mg
49
How does valgangciclovir compare to gangciclovir in regards to dosing?
900mg BID of valgangciclovir considered equivalent to 5mg/kg q12h of IV gangciclovir
- may be much more for an underweight patient
- about 60% bioavailable
50
What is required with foscarnet and cidofovir to reduce the risk of nephrotoxicity?
Extensive prehydration regimens with normal saline
51
Which drug is coadministered with cidofovir?
Probenecid
-reduces excretion of cidofovir into the renal tubules and lessens the toxicity
52
Is genotype based susceptibility testing available for CMV?
Yes
-performed if resistance suspected in patients not responding to gangciclovir
53
What does genotype based susceptibility testing for CMV reveal?
- whether gangciclovir resistance present
| - whether cidofovir or foscarnet are therapeutic options
54
What are gangciclovir and valgangciclovir first line drugs for?
Treatment and prevention of CMV infections
55
What is valgangciclovir often given for?
Prevent CMV infections after transplant
56
What is foscarnet used for?
- 2nd line agent for CMV
| - can also be used for severe or resistant HSV infections
57
What is cidofovir used for?
2nd line agent for CMV
58
What is something to consider when prescribing valgangciclovir?
- oral
- has good bioavailability
- adverse effects identical to those of gangciclovir (requires same rigorous toxicity monitoring as for IV gangciclovir)
59
Name the neuraminidase inhibitors?
- Oseltamivir (oral pro-drug)
- peramivir (IV)
- zanamivir (inhaled)
60
What are neuraminidase inhibitors used for?
Treatment or prophylaxis of influenza for those who cannot take the vaccine
-active against both A and B strains
61
What strains of influenza are amantadine and rimantadine good for?
Only A strains
62
How do neuraminidase inhibitors work?
Prevent the viral neuraminidase enzyme from releasing new virions from the host cell
-prevents further replication
63
What is the MOA of neuraminidase inhibitors?
Competitive inhibitors of viral neuraminidase
- an enzyme responsible for several functions of the influenza virus
- including release of new virions from infected cells
64
Are neuraminidase inhibitors active against any other viruses besides influenza?
No
65
How are the neuraminidase inhibitors tolerated?
Generally well tolerated
66
What are the adverse effects of oseltamivir use?
Transient effects
- nausea
- vomiting
- abdominal pain
67
What adverse effects of oseltamivir are more likely with prophylactic longer term use?
- headache
| - fatigue
68
What are the adverse effects of zanamivir use?
Mostly pulmonary effects
- cough
- bronchospasm
69
In what patients should zanamivir use be avoided?
With asthma or other reactive pulmonary diseases
70
What adverse effects does peramivir have?
No characteristic effects based on limited experience
71
When are neuraminidase inhibitors most effective?
When started early in the course of infection
-viral replication peaks early (48-72 hours after infection)
72
What does the package insert for neuraminidase inhibitors state about starting therapy in healthy adults with mild-moderate infections?
Should be started in patients who have been symptomatic for no more than 2 days
73
What does the package insert for neuraminidase inhibitors state about starting therapy in patients with severe infections?
Those that require hospitalization or vulnerable patients
- may be benefit even if therapy is delayed
- treatment guidelines recommend starting even if outside the "window" for these patients
74
Does resistance to neuraminidase inhibitors occur?
Yes
- currently zanamivir is active against vast majority of oseltamivir and peramivir resistant strains
- resistance patterns may change
75
What is important to remember about neuraminidase inhibitors for prophylaxis?
- not substitutes for the vaccine
| - adverse effects more common with prolonged use with prophylactic use than with shorter uses for treatment
76
What are the neuraminidase inhibitors good for?
Treating and preventing influenza infections
- if circulating strains are susceptible
- vast majority of data was with uncomplicated influenza
77
When is a good time NOT to start a neuraminidase inhibitor?
Otherwise healthy and flu has peaked and they are improving
-counsel about the vaccine for next season
78
What are interferons?
Normal human cytokines
- used by the immune system to activate cells when:
- infection is present
- fight cancerous cells
- other functions
79
For what diseases are interferons given exogenously?
- multiple sclerosis
- cancers
- viral hepatitis
80
What is the MOA of interferons?
Multiple MOA against hepatitis B and C
- different antiviral effects
- change cellular differentiation
- inhibit cell growth
- activate macrophages
- increase lymphocyte cytotoxicity
81
What are pegylated interferons?
Have molecules of polyethylene glycol (PEG) attached to the interferon molecules to improve their PK by increasing their half lives
-allows for decreased administration frequency
82
What interferons are used for HBV and HCV infections?
Interferon-α (alpha) 2a and 2b
-only pegylated forms currently recommended
83
What do the adverse effects of interferons cause?
Adverse effects are very common; lead to:
- noncompliance
- patient dropout
- avoidance of use
84
What are the most common adverse effects of interferons?
Flu-like symptoms
- headache
- fatigue
- weakness
- fever
- myalgia
85
What are some other common adverse effects of interferons?
- psychiatric
| - hematologic
86
Describe interferon psychiatric effects.
Depression is common
- often requires pharmacologic treatment
- patients with suicidal ideation should not be given interferons
Anxiety can occur
87
Describe interferon hematologic effects.
Cytopenias
- neutropenia
- anemia
- thrombocytopenia
88
What is usually the primary cause of anemia in HCV treatment?
Ribavirin
89
What can interferons worsen?
Decompensated cirrhosis
-generally not given to these patients
90
How often are pegylated interferons given?
Once weekly
91
How often are non-pegylated interferons given?
Three times weekly
92
What are the advantages of pegylated interferons?
- improved compliance and convenience
- adverse effects somewhat lessened
- efficacy is similar or somewhat higher
93
What affects interferon dosing?
- agent
- indication
- recommended dose of ribavirin also differs for each form for HCV infection
94
Which pegylated interferon is more effective for HCV infection?
Both have equivalent efficacy
95
For HCV infection, how is pegylated interferon-α 2a dosed?
Given as a fixed dose
96
For HCV infection, how is pegylated interferon-α 2b dosed?
Dosed by weight
97
Which pegylated interferon is FDA approved for HBV infection?
2a
-2b has been studied as well
98
In which conditions are interferons contraindicated?
Severe depression or patients contemplating suicide
- interferons commonly cause or exacerbate depression
- ensure that HCV patient's depression is controlled (pharmacologically if necessary) before starting; generally no rush to treat chronic HCV infection
- for HBV, other drugs are a better choice for depressed patients
99
For what infection has interferon use declined substantially?
HCV
-due to the advent of new direct-acting antiviral agents
100
What drugs are preferred over interferons for chronic HBV infection?
Nucleoside/nucleotide analogs due to much better adverse effect profile but are taken indefinitely
-interferons have a finite regimen
101
What is simeprevir?
HCV protease inhibitor
102
What is paritaprevir?
HCV protease inhibitor*
103
What is grazoprevir?
HCV protease inhibitor *
104
What is boceprevir?
HCV protease inhibitor
105
What is telaprevir?
HCV protease inhibitor*
106
What is daclatasvir?
HCV NS5A inhibitor
107
What is elbasvir?
HCV NS5A inhibitor*
108
What is ledipasvir?
HCV NS5A inhibitor*
109
What is ombitasvir?
HCV NS5A inhibitor*
110
What is sofosbuvir?
HCV NS5B (polymerase) inhibitor
111
What is dasabuvir?
HCV non-nucleoside polymerase inhibitor
112
What are combination directing acting HCV agents?
- paritaprevir/ombitasvir/ritonavir
- grazoprevir/elbasvir
- ledipasvir/sofosbuvir
113
Which 2 serine protease inhibitors were introduced in late 2011 for HCV infection?
- boceprevir
- telaprevir
- quickly became obsolete as more potent and better tolerated agents became available
114
What is the usual treatment duration for direct acting HCV agents?
3-4 months
- cure rates ranging from 80-100%
- much better tolerated than ribavirin plus interferon based regimens
115
What is the price of direct acting HCV agents?
Can be $1,000 per day
116
What are DAAs?
Direct acting antivirals
-along with ribavirin
117
What are indirect acting anti-HCV agents?
Interferons
-have indirect effects
118
Which HCV agents inhibit RNA polymerases?
- NS5B
| - non-structural
119
How do NS5A inhibitors work?
Not exactly clear
120
How are most direct acting HCV agents available?
Coformulated in fixed combinations
121
How many genotypes of HCV can cause infection in humans?
At least 6
-DAAs differ in their activity against each
122
Which genotype of HCV is the most prevalent in the US
Genotype 1 (comes as 1a and 1b)
123
How active are protease inhibitors against HCV genotype 1?
Have potent activity
124
Which protease inhibitors have limited activity against other HCV genotypes?
- simeprevir
| - paritaprevir
125
Against what HCV genotypes are NS5A and NS5B inhibitors active against?
Broad spectrum of activity against various HCV genotypes
126
Why is ritonavir added to ombitasvir and paritaprevir?
Solely as a PK booster
-has no anti-HCV activity
127
How are HCV DAA's tolerated?
Most are well tolerated; typically only mild toxicities
- nausea
- vomiting
- fatigue
128
What effects is simeprevir associated with?
Photosensitivity
- limit sun exposure
- wear sunscreen
Transient elevations in bilirubin
- frequently seen
- do not appear to be associated with significant hepatotoxicity
129
What effects is sofosbuvir associated with?
Symptomatic episodes of bradycardia
- rare
- almost all occurred in context of concomitant amiodarone
130
What effects is elbasvir/grazoprevir and ombitasvir/paritaprevir/ritonavir associated with?
Hepatic decompensation in some patients
- particularly in those with pre-existing cirrhosis
- closely monitor ALT
131
When is treatment interruption recommended when on elbasvir/grazoprevir and ombitasvir/paritaprevir/ritonavir?
- substantial asymptomatic elevations of ALT (> 10 fold ULN)
- lower elevations that are associated with symptoms of hepatitis
- jaundice
- nausea
- vomiting
- abdominal pain
132
What is the interaction profile of DAAs?
Lots of interactions
- CYP450
- P-glycoprotein
- organic anion transporter
- high prevalence of HIV-HCV coinfection (interactions with antiretrovirals)
133
Which DAAs are recommended to be administered with food?
- simeprevir
- ombitasvir/paritaprevir/ritonavir
- dasabuvir
134
For which DAA is presence of gastric acidity important for absorption?
- ledipasvir/sofosbuvir
- avoid acid-suppressing agents
- carefully time administration if must take them
135
For which patients is the addition of ribavirin or pegylated interferon to DAAs still recommended?
For some genotypes and patient populations
-cirrhotic patients
136
Does resistance to DAAs emerge during therapy?
Yes
-seems to correlate with failure to eradicate HCV
137
Which DAAs have the lowest genetic barrier for resistance?
- dasabuvir
- NS5A inhibitors
- simeprevir
138
Which DAAs have higher genetic barriers for resistance?
- other protease inhibitors
| - sofosbuvir
139
When is testing for DAA resistance mutations recommended before starting therapy?
- those with prior exposure to DAAs
- some patients with cirrhosis
- clinical significance of resistance mutations to DAAs is less well established than for HIV antiretrovirals
140
What types of infections is ribavirin used for?
- HCV (increases both effectiveness and toxicity of regimen when added on)
- respiratory syncytial virus (RSV)
- active against many different types of virus (influenza and adenovirus)
141
What is the MOA of ribavirin?
Not well characterized
- is a nucleoside analogue of guanosine
- phosphorylated into its active form inside cells
- technically a direct acting HCV antiviral but is considered separately from the DAAs
142
What is the main adverse effect of ribavirin?
Hemolytic anemia
- dose-related
- dose-limiting
- may be severe
143
Which other drug can exacerbate the anemia of ribavirin when coadministered for HCV?
Interferons
-cause cytopenias as well
144
What effects is ribavirin associated with?
- fatigue
- headaches
- insomnia
- difficult to determine whether these effects caused by ribavirin, interferons, or both (but clinically it doesn't matter what drug causes it just the fact that they must be monitored for)
145
Can ribavirin be used as monotherapy for HCV?
No
- rapidly leads to resistance
- must ALWAYS be used in combination
146
How is ribavirin usually administered?
Oral
147
What is aerosolized ribavirin used for?
Pulmonary RSV infection
- young children
- immunosuppressed adults
- lung
or
-hematopoietic stem cell transplants
148
Why is administering aerosolized ribavirin technically complex?
Efforts need to be made to reduce environmental exposures
- is a known teratogen
- studies show orally administered form may be just as effective
- many centers moving away from inhaled (at least in adults)
149
What pregnancy category is ribavirin?
Category X
- causes birth defects
- fertile women taking it should use reliable contraception
- pregnant women and healthcare workers should avoid aerosolized ribavirin
150
How is ribavirin-induced anemia primarily managed?
Dose reduction
151
How is ribavirin induced anemia managed if it becomes severe or persistent?
Erythropoietin can be given
152
When is ribavirin used for RSV?
Severe RSV
- aerosolized or oral
- children and adults
- primarily immunocompromised patients
or
-severe comorbidities
153
What must be monitored while on ribavirin?
Hemoglobin concentrations
-expect some degree of anemia
154
What is Entecavir?
HBV nucleoside analog
155
What is adefovir?
HBV nucleoside analog
156
What is telbivudine?
HBV nucleoside analog
157
Why can HBV nucleoside analogs compete for viral enzymes with native viral nucleosides?
Because HBV is a DNA virus
-similar competitive process as they do for reverse transcriptase
158
How does treatment with HBV nucleoside analogs differ from interferon based therapy?
- is prolonged
| - well tolerated
159
Which nucleoside/tide analog is drug of choice in both HIV and HBV?
Tenofovir
160
What is the MOA of HBV nucleoside analogs?
Inhibit the action of viral DNA polymerase
- take the place of nucleotides in the elongating strand of viral DNA
- leads to early termination of the viral DNA strain
161
Which viruses are HBV nucleoside analogs active against?
HBV
HIV
-not primarily used for HIV
162
How are HBV nucleoside analogs tolerated?
- very well tolerated by most patients
| - low incidence of adverse effects
163
What are some possible adverse effects with HBV nucleoside analogs?
- fatigue
| - elevations in creatinine phosphokinase (this may be associated with HBV itself rather than the drug)
164
What is an uncommon adverse effect of HBV nucleoside analogs?
-lactic acidosis
165
How do doses for HBV nucleoside analogs compare with HIV dosing?
HIV doses are higher than HBV doses
- patients with known HBV should be tested for HIV before starting therapy
- when using an analog (like lamivudine or tenofovir) for HBV/HIV co-infection, give in the higher HIV doses
166
Do HBV nucleoside analogs (plus tenofovir) cure HBV?
Are drugs of choice for HBV but do NOT cure it
-can repress it to the point that it does not progress
