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Flashcards in M15: Antivirals Deck (39)
1

Human Herpes Viruses (5)

HSV: Herpes Simplex virus

CMV: Cytomegalovirus

EBV: Epstein Barr virus

VZV: Varicella Zoster virus

HHV-8: Human Herpes virus 8

2

Associated Diseases of Human Herpes Viruses:

HSV: Herpes Simplex virus

CMV: Cytomegalovirus

EBV: Epstein Barr virus

VZV: Varicella Zoster virus

HHV-8: Human Herpes virus 8

Fever blisters, genital herpes, encephalitis

Retinitis, colitis, pneumonia

Mononucleosis, lymphoma

Chickenpox, shingles

Kaposi sarcoma

3

Associated Diseases of Other Viruses:

HAV: Hepatitis A virus

HBV: Hepatitis B virus

HCV: Hepatitis C virus

HPV: Human Papilloma virus

Influenza A and B

RSV: Respiratory Syncytial virus

HIV

Lassavirus

Enterovirus

Food-borne hepatitis A

Blood-borne hepatitis B

Blood-borne hepatitis C

Warts, cervical/anal cancer

Influenza

Bronchitis, pneumonia

AIDS

Lassa fever

Diarrhea, meningitis

4

Drugs that Treat Viral Diseases:

1) HSV
2) CMV
3) VZV
4) RSV
5) HBV
6) HCV
7) Influenza A
8) Influenza B
9) Lassavirus
10) Enterovirus
11) HPV

1) *(val)acyclovir, famciclovir, penciclovir, *foscarnet
2) *(val)ganciclovir, *foscarnet, cidofovir
3) *(val)acyclovir, famciclovir
4) *ribavirin, pavilizumab
5) *tenofovir, *emtricitabine, *lamivudine, entecavir, telbivudine, *adefovir
6) *interferon-α, *ribavirin, *telaprevir, *boceprevir, *sofosbuvir, *simeprevir
7) *amantadine, *rimantadine, *oseltamivir, *zanamivir
8) *oseltamivir, *zanamivir
9) *ribavirin
10) pleconaril
11) imiquimod, interferon-α

5

Immediately lethal viral infections:

Some viral diseases are immediately lethal and these are relatively (common / rare).

However, these outbreaks receive a lot of media attention, often out of proportion to the numbers of humans affected.

These viruses cause intense _ and patients die from _ or _.

Examples: (3)

rare

vascular inflammation
hemorrhage or pulmonary edema

Ebola, Yellow Fever, Hanta viruses

6

Self limited viral infections:

(Most / Few) viral diseases are self-limited; they cause an illness but then the host develops _ and eradicates the virus through _ and _ response.

a. The immunity can protect the host from re-infection _
Example: _

b. Immunity can be only for a _ duration while decreasing the severity of subsequent infections due to some remaining immunity
Example: _.

c. Some viruses can _ the acquired immunity of the host by changing the antigenic properties of its _
Example: _

Most
immunity
cytotoxic T cells and B cells

life-long
Hepatitis A

short
RSV

overcome
envelope
Influenza

7

Contained viral infections:

Many viral diseases are _ by the immune system, but are not _. These viruses establish themselves in the host.

a. Chronic persistent infection:

Some viruses cause a chronic persistent infection with _.

• Examples: Hepatitis C can cause _. HIV causes _.

b. Latent infection:

Other viruses remain latent and can _.

Most humans get infected with most of the human _ viruses before adulthood (HSV, VZV, CMV, EBV, HHV-6, HHV-7).

The primary illness is often _ although may not be recognized.

The viruses establish themselves and remain quiescent unless they reactivate spontaneously, due to _ or when the host gets profoundly _.

• Example: _ is caused by primary infection with varicella zoster virus (VZV), dermatomal reactivation can occur later in life in the form of _.

contained
eradicated

ongoing replication
liver cirrhosis
CD4 lymphocyte destruction

replicate during stress or immunosuppressive states

herpes

symptomatic

inflammation
immunosuppressed

Varicella (chickenpox)
zoster (shingles)

8

Immunization:
Active immunization-Vaccines:

Active immunization with a vaccine elicits an immune response by _ and/or _.

These may protect the host from infection when it encounters the virus for the _ time.

The immunity is often _ as long as the virus does not change its antigenic coat. There are 2 types of vaccines (2)

T-cells (cytotoxic T-cells) and/or neutralizing antibodies by B-cells

first

long-lasting

attenuated
inactivated

9

Immunization:
Passive immunization- Immunolobulin (Ig):

Passive immunization can protect the host from infection by receiving _ derived from _.

These preparations often contain a minimum titer of _ to be protective for specific viruses.

They neutralize the virus and block its infectivity by prohibiting _.

It (does / does not) elicit any immune response from the host and due to the (long / short) half-life of immunoglobulins (~2 weeks) the protection (is / is not) long lasting.

Recent advances in purification and sterilization made these products much safer than in the past. However, due to shortages and expense they are not widely used.

immunoglobulins
human serum

IgG

viral entry into cells

does not
short
is not

10

Principles of antiviral therapy:
Virucides:

These are agents that _

Examples (4)

They have a limited use in _ infections, warts (destroying host tissues and virus). Potential use in transmission prevention.

directly inactivate intact viral particles.

detergents, organic solvents, UV light, photodynamic inactivation.

mucocutaneous HSV

11

Principles of antiviral therapy:
Immunomodulation:

In some instances we can _ the host immune response to better contain or eradicate the virus infection.

a. Inducing host factors with antiviral properties:

Such as _ (cytokine) and _ (cytokine inducer).

They induce degradation of _, inhibit viral _, and enhance _ and _ cells activity.

b. Restoring host immunity:

In specific cases we can restore the host immune response by decreasing _ or treating the cause of the _ state.

Examples: A renal transplant patient may develop post-transplant lymphoproliferative disease (PTLD) from the reactivation of _ due to the immunosuppressed state.

By decreasing his immunosuppressant agents the host can now _ this reactivation but as a consequence may _.

In AIDS patients presenting with _ (HHV-8 or KSHV) we can treat this by starting the patient on antiretrovirals for HIV. The increasing _ count causes regression of the lesions.

stimulate

interferon
imiquimod

viral RNA
protein synthesis
cytotoxic T lymphocytes (CTL) and natural killer (NK)

immunosuppressant medications
immunosuppressed

EBV

contain
reject the kidney transplant

Kaposi sarcoma
CD4

12

Principles of antiviral therapy:
Antivirals:

These drugs inhibit viral replication at the _ level and they have a restricted spectrum of activity.

They target virus-specific proteins and have (high / low) affinity for host encoded proteins.

For example, acyclovir requires the viral enzyme _ for phosphorylation into its active form. This phosphorylation cannot take place in _ host cells

a. Antiviral drugs act only on _ viruses. Those viruses that are in a _ phase are not using their polymerase enzyme and therefore not susceptible to _. Active HSV replication (genital herpes) can be treated with this antiviral, but the latent HSV in the ganglion cells will not be affected.

b. They are often used too _ to make an impact. By the time patients are _ from the viral infection, billions of host cells have already been infected and several billions of viral particles have been produced.
• Example: _ for influenza is only effective within the first 48 hours of symptoms

c. Rapid development of drug resistance. The high replication rates of viruses require “_” polymerases that work very _ but are not _. Many _ mutations occur and most affect the infectivity. However, some mutations enable the virus to select for medication _. Drug resistane should be suspected when there is lack of clinical and virological response to therapy.

cellular

low

thymidine kinase (TK)
uninfected

replicating
quiescent
acyclovir

late
symptomatic
oseltamivir

sloppy
fast
precise
spontaneous
resistance

13

Mechanism of action of antivirals:
Antivirals for Herpes viruses:

a. Nucleoside analogues:

They prevent viral replication by directly inhibiting the _ and by incorporating a faulty _ causing termination of growing RNA or DNA chain.
- Antivirals: (4).

b. Nucleotide analogues:

They prevent viral replication by directly inhibiting the _ and by incorporating a faulty _ causing termination of growing RNA or DNA chain.
- Antiviral: (1)

c. Pyrophosphate analogue:

Inhibits _
- Antiviral: (1)

viral DNA or RNA polymerase
nucleoside
Acyclovir, valacyclovir, ganciclovir, valganciclovir

viral DNA or RNA polymerase
nucleotide
Cidofovir

viral polymerase
Foscarnet

14

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Acyclovir:

Mechanism of action:

Acyclovir (ACV) requires intracellular phosphorylation to _ which is the active drug.

The initial phosphorylation requires a viral kinase, called _, subsequent phosphorylations (2nd and 3rd step) by host cellular enzymes.

ACV-TP competitively inhibits _ and acts as a chain terminator due to absence of _.

Spectrum of activity:

_, _, and _ all of which encode the thymidine kinase.

However, there is a descending order of susceptibility (IC50); HSV-1>HSV-2>VZV) so _ or _ require higher doses.

It is important to note that the viral kinase produced by CMV has a very (high / low) affinity to acyclovir.

Extremely high doses of acyclovir would be required to halt the replication of _ thus acyclovir is not considered a drug of choice for infections due to _.

acyclovir-triphosphate (ACV-TP)

thymidine kinase (TK)

viral DNA polymerase
3’ hydroxyl group

HSV-1, HSV-2, and VZV

chickenpox or shingles

low

CMV
CMV

15

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Acyclovir:

Clinical use:

a. First episode of orolabial herpes-treatment offers _ symptomatic benefit.

b. Recurrent orolabial herpes (fever blisters): _ benefit in symptoms.

c. First episode of genital herpes: _ benefit in regard to symptoms and healing

d. Recurrent genital herpes: Symptomatic therapy; _ benefit in symptoms. _ therapy (80% reduction of recurrences). Reduces subclinical of viral shedding and transmission (but only by 50%)

e. _ herpes (baby infected from mother)

f. Herpes encephalitis: _ therapy is associated with better outcomes

g. Varicella (chickenpox) in adults with rash

significant

only 1/2 day

significant

only 1 day
Suppressive

Neonatal

prompt

3

adults over 50 years

immunocompromised

Post organ transplantation prophylaxis

16

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Acyclovir:

Product availability:

The drug is available in (3). Oral bioavailability only 15-30% due to its large_ (liver).

The clinical use for PO acyclovir is mainly for _ and _ (HSV). The IV formulation is used for serious HSV such as _, _ infections and treatment of both _ and _ infections in immunocompromised patients

Adverse effects:

Acyclovir is generally very well tolerated but can cause _ due to precipitation of the drug in renal tubules especially if the patient is not well _.

It can rarely cause _ side effects especially in the setting of renal failure when drug levels are high.

Resistance:

There are two resistance mechanisms of HSV to acyclovir.

Most important is the reduced or absent _. The first _ step does not take place and no _ is being produced.

Another pathway to resistance develops when the viral DNA polymerase has decreased affinity for _. Resistant isolates emerge after prolonged acyclovir treatment in immunosuppressed patients.

These resistant isolates are cross-resistant to _, but still sensitive to _ and _.

a pill form, intravenous (IV) and topical
first-pass effect

oral and genital herpes
encephalitis
VZV
HSV and VZV

acute renal failure
hydrated

neurologic

thymidine kinase (TK)
phosphorylation
active drug

ACV-TP

ganciclovir
foscarnet and cidofovir

17

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Valacyclovir:

Mechanism of action:
It is an _ of acyclovir and is converted to ACV by first-pass intestinal and/or hepatic _. Same mechanism of action as acyclovir.

Drug availability:
Available in a _ form. Its bioavailability is 3 to 5-fold (higher / lower) and therefore can be taken less often than acyclovir

Clinical use:
It is used to treat _ and _ infections. It has a (more / less) convenient dosing regimen for HSV infections as opposed to acyclovir. It is also preferred for VZV infections (chickenpox or zoster) because of the (higher / lower) drug levels required (IC50).

oral pro-drug
hydrolysis

pill
higher

HSV and VZV
more
higher

18

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Ganciclovir:

Mechanism of action:
It is a _ analogue and requires intracellular phosphorylation by a viral kinase called _. It inhibits the viral polymerase and DNA synthesis.

Drug availability:
It can be administered (3). The oral bioavailability is 5-9%.

Clinical use:
Mainly _ disease in immunocompromised patients: AIDS (_, _), solid organ transplant and bone marrow transplant recipients with CMV infection (_, syndrome or organ involvement).

Side effects:
Mainly (4)

Resistance:
After prolonged exposure to ganciclovir, mutations can occur on the _ kinase which will lead to ganciclovir resistance and in that case use of _ or _ is required.

nucleoside
UL97

PO, IV and intraocular

CMV
CMV retinitis, CMV colitis
CMV viremia

bone marrow suppression, headaches, fever, rash.

UL97 CMV
foscarnet or cidofovir

19

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Valganciclovir:

Mechanism of action:
It is a _ analogue and requires intracellular phosphorylation by a viral kinase called _. It inhibits the viral polymerase and DNA synthesis.

Drug availability:
It is available in a _ form only. It is the prodrug of _ with good bioavailability. After absorption the _ is removed during the first-pass through the liver and ganciclovir drug levels are similar to the IV administered formulation of ganciclovir.

Clinical use:
Mainly _ disease in immunocompromised patients: AIDS (_, _), solid organ transplant and bone marrow transplant recipients with CMV infection (_, syndrome or organ involvement). It is the preferred agent for treatment of _ infections post transplantation. Also it is the preferred agent for _ in transplant recipients at risk for CMV infection or reactivation post transplantation

Side effects:
Mainly (4)

Resistance:
After prolonged exposure to ganciclovir, mutations can occur on the _ kinase which will lead to ganciclovir resistance and in that case use of _ or _ is required.

nucleoside
UL97

pill
ganciclovir
valine

CMV
CMV retinitis, CMV colitis
CMV viremia
CMV
CMV prophylaxis

bone marrow suppression, headaches, fever, rash.

UL97 CMV
foscarnet or cidofovir

20

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Cidofovir:

Mechanism of action:
It is a monophosphate _ analogue and requires phosphorylation by _ enzymes only to become a _ cidofovir which is the active form of the drug. Unlike nucleoside analogues such as acyclovir or ganciclovir, cidofovir does not require _ by a viral kinase.

Drug availability:
Available in the _ form

Clinical use:
Major use is for _ resistant CMV infections in organ transplant recipients. It is also used in treatment of _ viral infections (which causes hemorrhagic cystitis and or nephritis in renal transplant patients) and it may have activity against _

Side effects:
Mainly (3)

nucleotide
cellular
diphosphate
phosphorylation

IV

ganciclovir
BK
smallpox

nephrotoxicity, GI intolerance and neutropenia

21

Mechanism of action of antivirals:
Antivirals for Herpes viruses:
Foscarnet:

Mechanism of action:
It is a _ analogue and inhibits the DNA polymerase of herpes viruses by reversibly blocking the _ (a necessary co-factor in the functioning of these enzymes). No _ is required for activity (not dependent on viral TK and requires no cellular phosphorylation).

Drug availability:
It can only be administered _.

Clinical use:
It has a broad antiviral spectrum against herpes viruses including (3). Mainly used in cases of HSV resistant to _ (TK deficient or mutation) and _ resistant CMV with UL97 mutation.

Side effects:
Major concern. It is directly toxic to _ leading to _ abnormalities (Ca, Mg, Phos, and K) and causes _ insufficiency. It can also cause _.

pyrophosphate
pyrophosphate binding site
metabolism

IV

HSV, CMV and VZV
acyclovir
ganciclovir

renal tubules
electrolyte
renal
penile ulcers

22

Mechanism of action of antivirals:
Antivirals for influenza viruses:

Ion channel blockers:

The viral ion channel, _ channel, maintains the _ across the viral membrane during cell entry. As the virus enters the cell by endocytosis, _ occurs.

This low pH activates the M2 channel to bring _ into the virion core leading to its disintegration and the release of viral _ into the _.

M2 channel blockers will bind to the M2 channel and sterically _ it. This will block the protons from entering the virion which then does not _.

-The _: _ and _

Sialic acid analogues (neuraminidase inhibitors):

The sialic acid analogues block _ by competitively inhibiting the viral _. They are also called neuraminidase inhibitors.

M2
pH
endosomal acidification

protons
nucleocapsid
cytoplasm

blocking
disintegrate

adamantanes
Amantadine and Rimantadine

the release of new virions
neuraminidase

23

Mechanism of action of antivirals:
Antivirals for influenza viruses:
Amantadine and Rimantadine:

Mechanism of action:
_ blockers.

Drug availability:
Both are available in _ and _

Clinical use:
Active against _ only. The M2 ion channel activity of influenza B is (higher / lower) than that of Influenza A to the point that it is completely _ to amantadine and rimantadine. They are effective if given _ in the course (within 36 hours). They also can be used for pre-exposure _ of influenza A (during flu season) or post-exposure _ (post contact).

Side effects:
They can cause reversible _ (dizziness, ataxia). This is more common with (amantadine / rimantadine) and especially seen in the _. Also they can cause _ and _.

Resistance:
Resistance can occur through mutations in the _ protein. It develops quickly in outbreaks and since 2006 most of the Influenza _ strains have been resistant.

Ion channel

capsules and liquid

Influenza A
higher
insensitive
early
prophylaxis
preemptive therapy

neurotoxicity
amantadine
elderly
nausea and dry mouth

M2
A

24

Mechanism of action of antivirals:
Antivirals for influenza viruses:
Oseltamivir and Zanamivir:

Mechanism of action:
_ inhibitors.

Drug availability:
Oseltamivir is available in a _ form while zanamavir exists in a _ form and is administered via _.

Clinical use:
These drugs are used for treatment of infections with _ (including H1N1 and possibly avian influenza) and _. They can also be used as prophylaxis and preemptive therapy. They are usually active against strains resistant to _.

Side effects:
Oseltamivir can cause _ and _. Zanamivir can cause _ and _ in addition to nausea vomiting and diarrhea. Zanamavir should be used in caution in patients who have _ or _.

Resistance:
Resistance to oseltamivir occurs (more / less) frequently then resistance to the adamantanes. In these cases of oseltamivir resistant strains _ usually is still active.

Neuraminidase

pill
powder
inhalation

influenza A
B
adamantanes

nausea and vomiting
bronchospasm and cough
asthma or COPD

less
zanamavir

25

Mechanism of action of antivirals:
Antivirals for viral hepatitis:

Antivirals for hepatitis C:
_: cytokine
_: inhibits viral RNA synthesis
Protease inhibitors: (4)

Antivirals for hepatitis B:
Nucleoside analogues: (4)
Nucleotide analogues: (2)

Interferon-α
Ribavirin
Telaprevir, boceprevir, sofosbuvir, simeprevir

Lamivudine, emtricitabine, entecavir, telbivudine
Tenofovir, adefovir

26

Overview of viral hepatitis:

Hepatitis A
– _ transmission
– Self limited disease (hepatitis)
– Immunity?

Hepatitis B:
– Transmission by _
– _ hepatitis or _ hepatitis, cirrhosis, liver cancer
– _ transmission from mother to the newborn causes _ in majority of cases (80%)
– Adult infection is mainly _ (90%) but it causes _ or _ (10%) with subsequent risk of cirrhosis and hepatocellular carcinoma
– Immunity?

Hepatitis C:
– Transmission by _
– Adult infection causes _ (90%) with subsequent risk of cirrhosis and hepatocellular carcinoma.
– Immunity?

Hepatitis D:
– Transmitted by _
– _ virus, co-infection with _ required
– Exacerbates _ infection

Hepatitis E:
– _ transmission
– Self limited except for _ (high mortality 30%)
– Immunity?

Oral-fecal
vaccine, HAV-Ig

blood/semen
Self limited, chronic
Perinatal, chronic active hepatitis (CAH)
self limited, carrier state or chronic hepatitis
vaccine, HB-Ig

blood/semen
chronic hepatitis
No immunity and no vaccine available

blood
Defective, Hepatitis B
pre-existing chronic Hepatitis B

Oral-fecal
pregnant females
vaccine is being licensed

27

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):

There are six major genotypes numbered 1 to 6 identified for HCV.

Genotypes _ to _ are by far the most common in western countries.

Almost 75 % of HCV infections in the US are HCV genotype _. HCV genotype _ compromise approximately 15% of infections and genotype _ less than 10%.

Since late 1990’s, the standard treatment of HCV infection had been a combination of _ and _ for 24 weeks (for HCV genotype 2 or 3) or 48 weeks (for HCV genotype 1).

The major aim of treatment is to achieve a _ which is defined as undetectable HCV RNA at 24 weeks after completion of treatment.

Patients infected with HCV genotype _ only have a 50% response rate compared to 75% in patients with genotype _ and _.

Monotherapy with either ribavirin or interferon (is / is not) efficacious.

The majority of patients suffer from (mild / severe) side effects and many are unable to complete therapy.

1 to 4

1, 2, 3

pegylated interferon (PEG-IFN)
ribavirin (RBV)

sustained virological response (SVR)

1
2 and 3

is not

severe

28

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):

_ against HCV are being developed.

In May, 2011 the FDA approved 2 first generation protease inhibitors (PI) _ and _.

Patients treated with one of those new agents in combination with _ and _ achieved higher SVR rates.

Recently in the fall of 2013 the FDA approved 2 second generation PI’s: _. The addition of second generation PI has led to achievement of SVR in up to 87% of patients infected with HCV genotype 1.

The addition of a PI to the standard regimen of _ and _ has become the new standard of care in the treatment of HCV infection.

(First / Second) generation agents are preferred over the (first / second) generation PI’s as they have a more favorable side effect profile and less drug-drug interaction.

Direct acting antivirals (DAA)

telaprevir and boceprevir

PEG-INF and RBV

simeprevir

PEG-IFN and ribavirin

Second
first

29

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Interferon-α:

Mechanism of action:
Is a cytokine with potent _ activity. After binding to receptors, interferon initiates a cascade of events that leads to various cellular responses such as inhibition of _, suppression of _, enhancement of the _ and augmentation of the specific _ of lymphocytes for target cells. _ have a longer half-life and are more effective.

Drug availability:
It is administered as _.

Clinical use:
HCV infection in combination with _, _.

Side effects:
_ symptoms (malaise, myalgias, fever), _ symptoms (depression), _, _, _, and _.

immunomodulatory
virus replication
cell proliferation
phagocytic activity of macrophages
cytotoxicity
Pegylated formulations (PegIFN)

subcutaneous injections

ribavirin, papillomavirus infection (HPV)

Flu like
neuropsychiatric
bone marrow suppression, rash, alopecia and retinopathy

30

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Ribavirin:

Mechanism of action:
It is a synthetic _ analogue of guanine. The mechanism of action is not fully understood. It requires intracellular phosphorylation by _ enzymes. It decreases the _ and inhibits viral _.

Drug availability:
It is available as _, _, and _ formulations

Clinical use:
It is active against many _ viruses and used in treatment of HCV infection in combination with _. RSV infections in high-risk _ and _ patients (pneumonia). _ virus infection in West Africa.

Side effects:
It causes (4).

nucleoside
host cellular
nucleotide pool
mRNA

PO, IV and inhaled

RNA
IFN-α
infants and immunocompromized
Lassa

hemolytic anemia, headaches, rashes and significant teratogenicity

31

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Protease inhibitors:

The HCV genome encodes a single _ that is ultimately cleaved into _.

Some of these smaller proteins are _ components of the virion and some are _ proteins required for ongoing viral replication.

NS3, a nonstructural viral protein and its cofactor NS4A form a _ that cleaves the HCV polyprotein into 4 structural and 6 nonstructural proteins.

Viral _ can initiate only after those proteins are cleaved.

NS3/4 Protease inhibitors will reversibly bind to the _ and inhibit HCV _.

_, cleaved from the polyprotein, is an RNA-dependent RNA polymerase.

NS5B inhibitors are _ analogue that inhibit the polymerase function halting HCV replication.

polyprotein
smaller proteins

structural
nonstructural (NS)

heterodimer serine protease (NS3/4A)

replication

active site NS3/4A
replication

NS5B

nucleotide

32

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Protease inhibitors:

Virus binding and internalization
(a); cytoplasmic _ and _
(b); internal ribosome entry site (IRES) mediated _ and polyprotein _
(c); RNA _
(d); _ and _
(e); virion _ and _

HCV RNA replication occurs in a specific membrane alteration, the _.

release and uncoating
translation, processing
replication
packaging and assembly
maturation and release

membranous web

33

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Boceprevir:

Mechanism of action:
_ generation _.

Drug availability:
Available _ three times daily.

Clinical use:
It is used in combination with _ and _ for treatment of naïve and treatment experienced patients infected with HCV genotype _.

Side effects:
(5). Multiple drug-drug interactions.

Resistance:
(High / Low) barrier for resistance thus they need to be used in combination with _ and _.

First
NS3/4A protease inhibitors

PO

PegIFN and ribavirin
1

Anemia, fatigue, dysgeusia, nausea and headache

Low
PegIFN and ribavirin

34

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Telaprevir:

Mechanism of action:
_ generation _.

Drug availability:
Available _ twice daily

Clinical use:
It is used in combination with _ and _ for treatment of naïve and treatment experienced patients infected with HCV genotype _.

Side effects:
Telaprevir’s most common side effects are _ and _. Rash does occur in up to 50% of patients. Fatalities have been reported in cases of severe _ so FDA issues a black BOX warning to discontinue all 3 drags (_, _, and _) if rash occurs with systemic symptoms. Other side effects include (8). In addition to multiple drug-drug interactions.

Resistance:
(High / Low) barrier for resistance thus they need to be used in combination with _ and _

First
NS3/4A protease inhibitors

PO

PegIFN and ribavirin
1

rash and pruritis
rash
telaprevir, PegIFN and ribavirin
anemia, nausea, hemorrhoids, anorectal discomfort, dysgeusia, fatigue, vomiting and anal pruritis

Low
PegIFN and ribavirin

35

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Sofosbuvir:

Mechanism of action:
_ generation _. It is a _ analogue that inhibits the _ polymerase.

Drug availability:
_ form administered orally daily.

Clinical use:

Approved in 2013 for the treatment of patients with genotype _ HCV infection in combination with _ and _. In naïve patients the rate of SVR was up to 89% after 12 weeks of therapy.

It can also be used for other genotypes. Combination of _ and _ is the first all oral regimen approved for treatment of HCV genotype _ and _ with SVR as high as 97%. Duration of therapy is 12 weeks for genotype 2 and 24 weeks for genotype 3.

Side effects:
_ tolerated. No significant side effects.

Resistance:
Resistant variants exist in (vivo / vitro) but do not appear to have an impact in (vivo / vitro) on the susceptibility of sofosbuvir.

Second
polymerase inhibitor
nucleotide
NS5B

Pill

1
PegIFN and ribavirin

sofosbuvir and ribavirin
2 and 3

Well

vitro
vitro

36

Mechanism of action of antivirals:
Treatment of Hepatitis C Virus (HCV):
Simeprevir:

Mechanism of action:
_ generation _ inhibitor.

Drug availability:
_ form administered orally once a day.

Clinical use:

Approved in 2013 for the treatment of patients with genotype _ HCV infection in combination with _ and _.

Combination _, _, and _ achieved SVR on up to 80 % of patients naïve to therapy or those who relapsed to prior combination therapy with PegIFN and ribavirin.

Side effects:
Well tolerated. Transient mild elevations of _ levels. _ and _ were reported as well.

Resistance:
Several mutations of _ are associated with reduced susceptibility to simeprevir.

Second
NS3/4A protease

Pill

1
PegIFN and ribavirin

simeprevir, PegIFN and ribavirin

bilirubin
Photosensitivity and rash

NS3/4A protease

37

Mechanism of action of antivirals:
Treatment of Chronic Hepatitis B:

Treatment is only indicated for patients with persistently positive _ and _.

_ chronic carriers with _ liver enzymes and a _ liver biopsy should not be treated.

Hepatitis B surface Antigen (HBsAg)
chronic active hepatitis (liver inflammation)

Asymptomatic
normal
benign

38

Mechanism of action of antivirals:
Treatment of Chronic Hepatitis B:
Lamivudine, Adefovir, Entecavir, Telbivudine, Emtricitabine and Tenofovir:

Mechanism of action:
These are _ analogues and suppress Hepatitis B viral replication by acting as chain terminators of HBV _ in _ of the genome.

Clinical use:
_ Hepatitis B infection.

Resistance:
The development of resistant mutations is common with _ use; 70% of HBV viruses are resistant to _ (YMDD mutation) within 4 years of treatment. Stopping these drugs may cause a flare-up of the hepatitis. Combination therapy with above drugs is being investigated and will likely be the treatment of choice in the near future, similar as in HIV

nucleoside/nucleotide
RNA
reverse transcription

Chronic active

prolonged
lamivudine

39

Immunization:
Active immunization-Vaccines:

a. Live attenuated vaccines:

These vaccines contain a live-attenuated virus. They elicit an _ response but they are too weak to cause _. However, in immunocompromized hosts they can cause _ and are therefore not safe for these individuals.

b. Inactivated viruses or recombinant proteins. These are completely safe to be used in _ individuals.

immune
disease
illness

immunocompromized