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Antimisiaris 2015
Antivirals Study Guide
Antiviral Agents
Explanation of Objectives:
These are very general objectives to help you understand the thought process of
antiviral medication management.
For the purposes of the exam, the practice questions represent the topics and
format of questions you will see. The practice questions focus on general
mechanisms of how antiviral agents work, adverse drug events (reactions) per drug,
or class of drugs that are notable, and highlights of clinical uses.
Dr. Ds understanding is that for Step 1, the knowledge is much less detailed than
our soft chalk, focusing on general categories of antivirals divided along HIV and
non-HIV medications. Mechanism of viral suppression/antiviral activity by class and
having a good idea of which drugs are in which class, clinical use, toxicity highlights,
mechanism of resistance if it is a ubiquitous drug such as acyclovir- [the HIV
mechanisms of resistance are so numerous, that is should be sufficient to
understand that the virus mutates frequently and resistance is an ongoing and
complex problem.] As for renal dose limitations, you will not likely be asked those
on step 1.
1) Describe why overall antivirals have higher toxicity than antibiotics.
a) This is straight forward. They are intracellular and more invasive than other
drug classes which have extracellular targets.
b) The number of toxicities that involve comorbid conditions is also high
because of the invasive nature of this class of drug.
c) Because of a & b, it is difficult to generalize with regards to toxicities even
within classes of antiviral agents.
2) Compare and contrast antiviral clinical efficacy.
a) Be familiar with agents that possess improved efficacy with less toxicity, but
may have the tradeoffs of costs or limited spectrum of use, or agents that
can be used to combat more than one type of virus (i.e. agents that apply
to HCV but not HBV vs agents which are used for both HIV and HBV)
b) The charts in this review are most useful here
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Antivirals Study Guide
3) Know common antiviral agent adverse effects and approaches to treatment of
adverse effects.
a) Side effects that need to be managed aggressively vs those which can just
be managed using other treatments for the benefit of antiviral therapy.
Dylipidemias with ARV treatment in HIV are just managed and not usually a
reason to DC drug use, whereas severe lactic acidosis can be
lifethreatening.
b) In other words: do not memorize each and every side effect for each and
every drug, but have awareness of the common ADEs, highlighted
recommendations.
4) Be familiar with major antiviral classes and common specific agents.
a) Dont memorize each and every antiviral agent.
i) For example, you can look up what is in various HIV combination agents,
but its helpful to familiarize yourself with individual classes of agents
because some treatment recommendations recommend treatment by
class combinations.
ii) Most antiviral taxonomy (drug class) centers on where in the viral
replication cycle the drug works.
(1) You might have a drug which is part of HIV, HCV, HBV, and treatment
recommendations because they work at one common point of viral
replication.
(a) For example: direct acting antivirals which are approved for use in
chronic HBV treatment are all nucleot(s)ide analogues.
(i) Lamivudine (Epivir-HBV) approved for HIV and HBV, adefovir
dipivoxil (Hepsera) approved for HBV, entecavir (Baraclude)
approved for HBV, telbivudine (Tyzeka) approved for HBV and
tenofovir disoproxil fumarate (Viread) approved for HIV and
HBV.
1. They all inhibit reverse transcriptase/polymerase activity,
thus decreasing viral replication.
2. They all have black box warnings regarding increased HBV
exacerbation with discontinuation of use, as well as risk of
lactic acidosis and severe hepatomegaly with steatosis.
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Antivirals Study Guide
5) Explain comorbidity limitations to use of some antivirals.
a) Awareness of toxicities associated with antiviral use should be applied to
assessment of risk with regard to use of specific agents in patients at
increased risk of exacerbation of underlying comorbid diseases.
b) Example: HIV and HBV co-infected patients- you have to consider the effect
on HIV and the effect on hepatic disease as well as resistance in the case of
both. HIV drugs can cause hepatic problems, and both can have variable
effects on resistance of either virus. (This is why the guideline site is very
important for HIV treatment-its ever changing, and no, you dont have to
memorize them, just be aware that this is a challenge in management)
https://aidsinfo.nih.gov
(End Objectives)
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Antivirals Study Guide
Entacavir (ETV)
Tenofovir (TDF)
Emtricitabine/Tenofovir
Lamivudine (LMD)
1. In HIV therapy, Integrase Inhibitors target the enzyme responsible for viral
DNA integration into host DNA. What is the most significant concern when
using this class of drugs?
a. Lactic acidosis
b. Diarrhea, headache, N/V
c. Intracranial hemorrhage
d. Resistance
2. A patient who is being treated for HCV infection becomes pregnant. She has
been receiving PEG Interferon and ribavirin for 8 weeks. She should continue
on this regimen because she responded very well at 4 weeks and only has 4
more weeks to complete this course of treatment.
a. True
b. False
3. Your patient is diagnosed with HCV and now its time to start treatment. You
wish to avoid the use of Interferon because this patient has a history of
suicidal ideation and major depressive disorder. Which of the following
options would you consider?
a. Simeprevir (SIM)
b. Boceprevir (BOC)
c. Sofobuvir (SOF)
d. None of the above
4. There is an H1N1 influenza outbreak and you are getting lots of patients
asking for anti influenza drugs. What medications are options for
treatment?
a. oseltamivir and zanamivir
b. xanamivir
c. Amantadine, Rimantadine, Ostelamivir, and Zanamivir
d. All of the above
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Antivirals Study Guide
5. Every time your patient goes out in the sun, she gets a herpes outbreak on
her lips. She has been using acyclovir gel to treat the outbreaks but this
time, they are recurring with increased frequency and taking much longer to
heal. Should the strategy for treatment change?
a. We could try penciclovir
b. No, she is just out in the sun more often and changing therapy will
result in treatment failure.
c. We could try oral ganciclovir
d. We could try valciclovir oral
Hepatitis B
Goal of therapy is suppression to undetectable levels to reduce the risk of cirrhosis
and hepatocellular carcinoma. Measures of response: normalization of liver function
tests, HBV seroconversion, decreased evidence of viral replication (HBV DNA IU/mL
decreases).
Usually HBV can resolve spontaneously. (95% of adults recover fully without
complications but younger age of infection results in greater risk of chronic
HBV and greater risk of hepatocellular carcinoma.
Hepatocyte damage occurs due to T cell cytolytic response to lyse infected
hepatocytes
Symptoms of severe liver failure: encephalopathy, coagulopathy (increased
PT/INR), jaundice, ascities, spider angioma, fatigue.
Duration of Therapy: oral antiviral therapy usually is given for 12 months after
seroconversion, but long time follow up is required due to risk of persistence of the
latent virus and many patients ultimately require lifelong therapy.
Special populations:
o HIV coinfection
Vaccinate against HBV (4 intradermal low doses better than 3 IM
standard doses)
Do Not Use Telbivudine (TBD) due to risk of resistance, and avoid
LMD (lamivudine), ETV (entecavir) & AFV (adefovir) due to
increased risk of resistance and therapeutic limitations
Good choices are Tenofovir (TDF) IN COMBINTION with
Emtricitabine (FTC) or other combo products which also contain
FTC in triple combo
o Immunosuppression / Chemotherapy patients
o Liver transplant patients, some regimens more effective than others
o Renal Failure/transplant patients
All oral antiviral agents require dose adjustment in renal
impairment
Vaccination is less effective in this population
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Antivirals Study Guide
o
Interferon: IFN induced host antiviral gene expression to inhibit virus replication,
protein synthesis, and assembly. Also, enhances immune response.
Oral Medications:
Currently, chronic HBV cannot be cured as can HCV. The reason being that HBV is
a DNA virus which primarily infects hapatocytes nuclear DNA and HBV intrahepatic
DNA is difficult for the current therapy (HBV polymerase inhibitors which are reverse
transcriptase inhibitors RTIs) to get at.
The reason we use reverse transcriptase inhibitors on HBV, a DNA virus, is that HBV
has the peculiarity of replicating via reserve transcription of an RNA intermediate
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Antivirals Study Guide
which allows nucleoside reverse transcriptase inhibitors to be effective in controlling
replication of HBV.
-compare and contrast: unlike HCV where medications used for the treatment of
HCV have limited intrinsic and anti-HIV effects, many, if not all HBV medications
demonstrate activity against HIV.
Emergence of resistance to HIV therapy is a concern.
Hepatitis C
Goal of therapy is eradication of the HCV.
HCV related glomerular disease is common, and impaired renal function both limits
safety of antiviral drug use as well as presents a comorbid illness to be addressed
during therapy since HCV can worsen renal function.
HCV is an enveloped, positive-sense, single-stranded RNA virus classified within the
genus hepacivirus in the Flaviviridae family.
Currently, HCV isolates are classified into seven major genotypes, i.e., genotypes 1
through 7, and an array of subtypes.
HCV genotypes differ by 20%35% in genome sequence, whereas subtypes within
each genotype can differ by least 15%.
Genotype 1 is the most prevalent (46%), followed by genotype 3 (30%); genotypes
2, 4 and 6 (cumulatively approximately 22%); and genotype 5 (less than 1%).
Different genotypes exhibit distinct geographic distributions:
D.Antimisiaris 2015
Antivirals Study Guide
pleasant or preferred
treatment due to flulike
symptoms and depression,
mypopathy, injection site
reactions, malaise and
fatigue, increased liver
function tests, insomnia,
impaired concentration,
irritability, and neutropenia.
infection.
D.Antimisiaris 2015
Antivirals Study Guide
INF can be used alone to treat HCV but typically is used with ribavirin (which is
known for limitations because it causes anemia)
DAAs (Direct Acting Antivirals as opposed to interferon)
Recently, the use of active direct-acting antiviral molecules to block HCV infection
has led to substantial improvements in sustained virological response rates in
genotype 1-infected patients.
However, IN THE FUTURE, JUT FYI, the use of these drugs may allow selection of
resistant variants if direct-acting antiviral monotherapy is adopted, and a high
relapse rate occurs after direct-acting antiviral treatment is discontinued.
Special Considerations in Treatment:
Medications Highlights:
A detailed table of HCV treatments accompanied soft chalk on antivirals for your
reference.
Key Points:
Combination Direct Acting antivirals (non- ribavirin type) are able to achieve
sustained virologic response (SVR) 12 weeks after discontinuation of therapy,
of >95%. *which studies have shown is an indicator that 6 month SVR will
occur.
o In other words, these are successful interferon free regimens.
o RVR (rapid viral response to therapy) is best predictor of SVR.
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Antivirals Study Guide
Ideal is to avoid IFN and ribavirin (i.e using oral combination therapy see
chart).
Refer to guidelines at time of treatment decision- genotype, relapse, and
futility rules impact decisions. They are complex as in HIV.
o Futility rules means for example if you have a patient on triple therapy
( PEG INF + ribavirin + beoceprevir) and you test HCV RNA and the
level at treatment week 12 of >100IU/mL or detectable at TW24 then
you would DC triple therapy.
o Complex recommendations: example
Be familiar with various drugs ADEs and thats enough for now, dont
memorize guidelines.
Ribavirin (RBV)
RNA polymerase inhibitor
Directacting Antiviral Agents: HCV Protease (NS3/4A eg. paritaprevir) & NS5B polymerase nucleotide.
Combined with PEGIFN & RBV in HCV genotype 1 to SVR rates from ~40% to ~7095% & decrease length of
therapy, but AE as compared to
interferon sparing regimens. Interferon sparing regimens may be considered if: PEGI intolerance, other
concomitant auto immune disorders, decompensated liver dx, severe depression, decrease neutrophils/Hgb or
cardiovascular dx. (FYI dont memorize)
Boceprevir (BOC)
Contraindication: Monotherapy,
concurrent therapy with high risk
medications (i.e. antiarrhythmics, and
others which result in severe ADEsstatins and myopathy)
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Antivirals Study Guide
Simeprevir (SIM)
Telaprevir (TVR)
NS5B nucleotide (eg. Sofosbuvir) & nonnucleoside (eg. Dasabuvir) polymerase inhibitors
and combo products
Sofobuvir (SOF)
Sovaldi
Contraindication: Monotherapy
ADEs: fatigue, HA, Nausea, Insomnia,
Neutropenia
Drug Interactions: p-gp substrate:
anticonvulsants and rifampin, tipranavir
and ritonavir can decrease SOF levels.
Caution with Amiodarone (decreased
HR) $50K for 12 weeks
Fatigue, HA, N/V/D, insomnia, may
increase glucose, bilirubin
Same drug interactions as Sovaldi
plus proton pump inhibitors
(omeprazole etc) and H2 blockers
(ranitidine) can change gastric pH and
alter absorption of LDV.
NOTE- not a monotherapy
$94K 12 weeks, $189K for 24 weeks
Just be aware for later
HIV Treatment
95% adherence to regimen is required to slow resistance
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Antivirals Study Guide
D.Antimisiaris 2015
Antivirals Study Guide
Influenza
Vaccination is the main antiviral defense. Especially: healthcare workers,
high risk patients such as the elderly.
Route of
administrat
ion
Dosage
Forms
Prophylaxis
Treatment
Amantadine
Rimantadine
(analog of
amantadine)
Oral
Oseltamivir (Tamiflu)
Zanamivir
(Relenza)
Oral
Oral Inhalation
(<2% oral
bioavailability)
Capsules, syrup
disk haler
No: lots of
resistance
No: resistance
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Antivirals Study Guide
Renal dose
adjustment
ADEs
Comments
>99% except if
severe H5N1 may
combo thx w NI
Yes
Multiple because
of pro-dopamine
effects, CNS,
irritability,
insomnia,
dizziness, GI
upset
Better CNS
toxicity with
reimantidine
Helps in
institutional
outbreaks
(nursing homes)
to prevent spread
of influenza.
Avian isolates are
resistant to
amantadine
Overall not used
much due to
resistance
Yes
No
Nausea/V/insomnia,
bronchitis, HA,
elevated LFTs
Behavior changes in
kids
Probenecid increases
levels
May cause
bronchospasm in
asthma or COPD
patients (dry
powder
formulation)
People stockpile
for avian and
swine flu (H5N1
and H1N1)
*Pramivir, an IV
agent is more
potent than
zanamivir against
H1N1 Influenza A.
NOTE: This information can change from year to year, especially with regards to H1N1
and other rapidly changing viruses.
D.Antimisiaris 2015
Antivirals Study Guide
Valacyclovir
Prodrug formulation of
acyclovir, rapidly and
completely converted
to active form.
SAME MOA as acyclovir
Penciclovir
(Denavir)
SAME MOA as acyclovir
Famciclovir
Resistance is common
Well tolerated rare CNS
side effects
Same, same as
acyclovir. Simplified
dosing and more costly
Oral valacyclovir
bioavailability if just
about like IV: prodrug of
acyclovir
Poor oral availability:
only topical formulation
-used if topical and oral
together fail
(valcyclovir and
acyclovir)
Prodrug of penciclovir
Same, same.
Not as much
resistance.
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Antivirals Study Guide
(Famvir)
SAME MOA as acyclovir
and VZV
Nephrotoxic
Recommended prehydration with normal
saline (IV NS) and
adding oral probenecid
just prior to
administration of
cirofovir (probenecid
blocks kidney
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Antivirals Study Guide
concentration of other
drugs)
Drugs used to treat Respiratory Syncytial Virus Infections (RSV)
Ribavirin
RSV, Influenza A, and B Multiple toxicities (see
Hep c drugs): nausea,
anemia, lethargy
Palivizamab
RSV
Hypersensitivity
(Synagis)
Only used in children
Thrombocytopenia
Binds to A antigenic
Rash
site of RSV F protein
Fever
Is a Monoclonoal
Antibody
7. In HIV therapy, Integrase Inhibitors target the enzyme responsible for viral
DNA integration into host DNA. What is the most significant concern when
using this class of drugs?
a. Lactic acidosis
b. Diarrhea, headache, N/V
c. Intracranial hemorrhage
d. Resistance
Answer: b, Diarrhea, HA, N/V
8. A patient who is being treated for HCV infection becomes pregnant. She has
been receiving PEG Interferon and ribavirin for 8 weeks. She should continue
on this regimen because she responded very well at 4 weeks and only has 4
more weeks to complete this course of treatment.
a. True
b. False
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Antivirals Study Guide
Answer: False, ribavirin is contraindicated in pregnancy
9. Your patient is diagnosed with HCV and now its time to start treatment. You
wish to avoid the use of Interferon because this patient has a history of
suicidal ideation and major depressive disorder. Which of the following
options would you consider?
a. Simeprevir (SIM)
b. Boceprevir (BOC)
c. Sofobuvir (SOF)
d. None of the above
Answer: d, none of the above because monotherapy with direct acting agents if not
recommended.
10.There is an H1N1 influenza outbreak and you are getting lots of patients
asking for anti influenza drugs. What medications are options for
treatment?
a. oseltamivir and zanamivir
b. xanamivir
c. Amantadine, Rimantadine, Ostelamivir, and Zanamivir
d. All of the above
Answer: all of the above can work for H1N1
11.Every time your patient goes out in the sun, she gets a herpes outbreak on
her lips. She has been using acyclovir gel to treat the outbreaks but this
time, they are recurring with increased frequency and taking much longer to
heal. Should the strategy for treatment change?
a. We could try penciclovir
b. No, she is just out in the sun more often and changing therapy will
result in treatment failure.
c. We could try oral ganciclovir
d. We could try valciclovir oral
Answer: d-try oral valacyclovir because she is using topical acyclovir as of
now, and she can next add oral therapy which is a bit more potent using
acyclovir or valacyclovir. She shouldnt use ganciclovir due to toxicity and
that its indicated for CMV, b is just not accurate, a penciclovir would be a
next step if she seems to have resistant virus to oral and topical acyclovir
products.