6/11- Antiviral Therapy Flashcards
1
Q
Options for the Control of Viral Infections (broad)?
A
- Antivirals
- Isolation/quarantine (depends on pathogenesis and transmission route)
- Immunization (active; passive*)
- Immunomodulators
- Other: drug/alcohol use, physical activity, risky behaviors…
* e.g. Hep B in babies born to chronic Hep B mothers given Hep B Ig
2
Q
Potential targets for antiviral agents?
A
- Adsorption
- Penetration
- Uncoating
- Early transcription
- Early translation
- Genome replication
- Late transcription
- Late translation
- Assembly
- Release
Want to target unique viral functions (limits toxicity)
3
Q
What is key for the treatment of acute viral infections?
A
Early initiation of therapy (similar to Abx)
4
Q
What are the most common causes of viral respiratory infections?
A
- Influenza
- RSV
5
Q
Disease course of influenza?
Typical treatment?
What are some complications of influenza?
A
(Outbreaks each year)
Course of disease:
- Uncomplicated influenza typ gets better w/ or w/out treatment (symptomatic treatment- rest, OTC meds, fluids)
Complications:
- Bacterial infections
- Viral pneumonia
6
Q
Treatment for influenza (1 method…oldish)? Mechanism?
Route?
Indications?
Resistance?
A
Amantidine and Ramantidine (trycyclic amines)
(not used anymore)
- Mechanism: interferes with uncoating
- Indications: prevention and treatment of influenza A virus infections
- Resistance: associated with mutations in the M2 protein (why these aren’t used so much)
**not effective for Influenza B
7
Q
How many strains of influenza circulate in a year?
A
Three:
- A (H1N1)
- A (H3N2)
- B
8
Q
Efficacy of amantadine/rimantidine for influenza?
A
- Drugs decreased fever and virus shedding
- More rapid improvement in symptoms and activity levels
9
Q
What other drugs (not targeting uncoating) can be used to treat Influenza?
- Mechanism:
- Route:
- Adverse effects:
- Indications:
A
- Neuraminidase inhibitors (sialic acid analogs)
- Mechanism: inhibit viral neuraminidase
- Route: oral (oseltamivir) or inhaled (zanamivir)
- Adverse effects: nausea/vomiting with oral oseltamivir; bronchospasm with inahled zanamivir
- Indications: Influenze A AND B infections (treatment and prophylaxis)
10
Q
Which are preferred for the routine prevention of influenza: vaccines or antivirals?
A
Vaccines!
11
Q
Which strains of influenza are resistant to Amantadine? (those that inhibit uncoating)
Alternative?
A
- A: H3N2
- A: H1N1
Alternatively use Oseltamivir or Zanamivir
12
Q
Those at high risk for influenza complications?
A
- Children < 2 or adults > 65
- Chronic pulmonary (asthma), cardiovascular (not just HTN), renal, hepatic, hematological (sickle cell), metabolic (DM), or neurologic/neurodevelopment conditions
- Immunosuppression
- Pregnant/postpartum women (within 2 wks)
- < 19 and receiving long-term aspirin
- American Indians/Alaskan natives
- Morbidly obese (BMI > 40)
- Residents of nursing homes and other chronic-care facilities
13
Q
What is Tamiflu?
A
Oseltamivir
14
Q
What is Ribavirin?
- Mechanism
- Route
- Adverse effects
- FDA Indications
- Uses
A
Guanosine analog
- Mechanism: multifactorial; alters nucleotide pools and mRNA formation
- Route: aerosol (RSV), oral (HCV), IV
_- Adverse effect_s: anemia, bronchospasm, teratogenic and mutagenic
- FDA Indications:
—-Severe RSV dz in infants
—-Chronic HCV (with PEG-IFN)
(also Lassa fever and Hantavirus infections)
Treatment for bronchiolitis: allowed earlier termination of ventilation
15
Q
What are some common herpes viruses to consider?
A
- Herpes simplex
- Varicella-zoster
- CMV
16
Q
What can be used to treat herpes viruses?
A
Acyclovir (guanasine analog; anti-viral)
17
Q
What is acyclovir?
- Mechanism
- Route
- Adverse effects
- Indications
A
Guanosine analog (anti-viral)
- Mechanism: inhibits VIRAL TK, DNA pol; results in DNA chain termination
- Route: oral, IV, and topical form
- Adverse effects: phlebitis, headache, nausea, CNS toxicity, and crystalluria
Indications:
- Genital, perinatal, and CNS HSV
- Varicella and zoster
- HSV infections in immunocompromised hosts
18
Q
What is one of the worst complications of HSV?
What can be used to prevent this?
A
HSV Encephalitis
(high morbidity/mortality rate)
Acyclovir
- Better results than older methods for all Glasgow levels
- Should start IV acyclovir for anyone who presents with altered mental status who may have HSV encephalitis until diagnostics come back
19
Q
Who should be treated for Varicella?
A
- Immunocompromised
- Possibly pregnant women
- Adolescents and adults
- Patients at high risk for complications
(Acyclovir for normal toddlers and children under 10 is efficacious but often not necessary)
20
Q
What are some “off-label” uses of acyclovir?
A
Herpes simplex viruses:
- Gingivostomatitis
- Cold sores (penciclovir)
- Whitlow
- Ocular infections*
- Proctitis
- Eythema multiforme
*topical therapy is approved for use; other drugs available
Varicella-zoster virus
- Pneumonia
- Encephalitis
21
Q
How do famciclovir and valacyclovir differ from acyclovir?
A
They are prodrugs and have greater oral bioavailability than acyclovir
22
Q
What are famciclovir and valaciclovir used for?
A
Treatment of shingles
Suppression of genital HSV
Valacyclovir: primary genital HSV
Famciclovir: mucocutaneous HSV in immunocompromised
23
Q
What is a drawback of acyclovir? Which form?
A
If given orally, have to take many times a day (poor compliance)
24
Q
Valacyclovir has been associated with what in certain types of patients? Which patients?
A
TTP/HUS (hemolytic uremic syndrome)
- Pts with advanced HIV infection
- Bone marrow and renal transplant recipients
25
What drugs can be used to treat/suppress CMV infections? Routes of administration?
- Ganciclovir (IV)
- Valganciclovir (PO)
- Cidofovir (IV)
- Foscarnet (IV)
26
What is the major toxicity associated with **ganciclovir**?
Neutropenia
27
What is the major toxicity associated with **valganciclovir**?
Thrombocytopenia
28
What is the major toxicity associated with **Cidovir**? What kind of drug is it?
- Hematologic
- Renal
- Eye
- Neurologic
- GI
(nucleotide analog)
29
What is **Foscarnet**?
What is the major toxicity associated with it?
**Pyrophosphate** analog **(IV for CMV**)
- **Renal** (careful in pts with renal insufficiency)
- Neurologic
- Mineral/electrolyte abnormalities
30
**T/F:** if you are vaccinated for varicella (rather than contracting the disease) you are not at risk for Herpes zoster (reactivation)
**False**! Live vaccine, so can later get reactivation (just as if contracted the disease in the first place)
31
What an be used to treat **chronic HBV** infections (broadly)?
- **Interferon alpha** (cytokine), including PEG-IFN
- **Nucleoside/tide analogs** (DNA/Pol RT inhibitors)
32
**Interferon alpha**?
- Mechanism:
- Route:
- Adverse effects:
- Indications:
- _Mechanism_: induces **antiviral state** via induction of cellular genes
- _Route_: **parenterally** (only)
- _Adverse effects_: **flu-like** symptoms (feel crappy, fatigue, malaise), hematologic, neurologic, hepatic, and renal toxicity
- _Indications_: **chronic HBV and HCV**, **HPV**, and **HHV8** infections
33
What are some nucleoside/tide analogs that can be used to treat chronic HBV?
Most commonly used?
- **Lamivudine** (S)
- **Adefovir** (T)
- **_Entecavir_** (S)
- **Telbivudine** (S)
- **_Tenofovir_** (T)
(Tide/Side)
Most common (if no HIV): **Entecavir** and **Tenofovir**
34
T/F: Acyclovir can be used to treat CMV
**False**; must use ganciclovir or falganciclovir (or cidofovir or foscarnet)
35
What are the adverse events/toxicity associated with chronic HBV treatment with: **Lamivudine**?
Many people develop resistance, so never used by itself to treat HBV
- Fatigue
- HA
- Abdominal pain
- Myalgia
- Nasal symptoms
- Pancreatitis
36
What are the adverse events/toxicity associated with chronic HBV treatment with: **Adefovir**?
- Fatigue
- HA
- N
- Abdominal pain
- Nephro and hepatotoxicity
37
What are the adverse events/toxicity associated with chronic HBV treatment with: **Entecavir**?
- Lactic acidosis
- HA
- Diarrhea
- Arthralgia
- Insomnia
38
What are the adverse events/toxicity associated with chronic HBV treatment with: **Telbivudine**?
- Lactic acidosis
- Myopathy
- Neuropathy
39
What are the adverse events/toxicity associated with chronic HBV treatment with: **Tenofovir**?
Hepato and **nephrotoxicity** (biggest worry is renal insufficiency; monitor phosphorous levels)
(No reported resistance)
40
What are the preferred treatments for **chronic HBV** invection?
- **Tenofovir** and **entecavir** preferred for initial treatment
- Combo therapy for HIV/HBV coinfection, ts with drug resistance, and with decompensated cirrhosis
(e. g. **Tenofovir + Lamivudine**)
41
What are the endpoints of therapy in HIV negative pts treated for chronic HBV
- HBeAg, seroconversion
- Elimination of detectable virus
- ALT \< 0.5 ULN
42
**What is Hep C?**
- Genetic material
- How many "genotypes"
- Integrates into human genome (Y/N)
- Transmission
- Progression of disease
Genetic material: **RNA**
How many "genotypes": **6**
**DOES NOT** integrate into human genome
**Transmission:**
- Blood exposure
- Sex
- Occupational
- Peri-natal
**Progression of disease:**
- Slow progression to liver fibrosis and cirrhosis
- Accelerated by HIV and alcohol use
43
How was HCV **previously** treated? Side effects?
One regimen with a complex algorithm:
- **Pegylated IFN** (injected once weekly with many side effects, such as **depression and fatigue**)
- **Ribavirin** (weight-based dosing 2x daily with side effects such as **anemia, rash**, etc.)
44
Targets for direct acting antivirals (HCV)?
- **NS3/4 protease inhibitors** (translation and polyprotein processing)
- **NS5B** **polymerase inhibitors** (nucleosides, non-nucleosides) to inhibit RNA replication
(- Receptor binding and endocytosis)
(- Transport and release)
45
What drugs can be used to treat **HCV**? Drug classes for each?
- **Telaprevir** (NS3/4A protease inhibitor)
- **Boceprevir** (NS3/4A protease inhibitor)
- **Sofosbuvir** (NS 5B "nucleotide' polymerase inhibitor)
- **Simeprevir** (NS 3/4 protease inhibitor, GT 1 only)
- **Ledipasvir/sofosbuvir (Harvoni)** (NS 5A replication complex inhibitor/NS 5B)
- **Ombitasvir/paritparevir/r, dasabuvir (Viekira)** (NS 5a, PI/r, NS5B non-nucleoside polymerase)
46
Therapy for **chronic Hepatitis C**?
**Old**: Pegylated IFN + ribavirin + protease inhibitor
**New**: oral protease inhibitor therapies
47
Therapy for acute Hepatitis C results in what?
Possible reduction in the frequency of chronic hepatitis
48
Treatment for advanced liver disease (cirrhotic) pts has been shown to do what?
Inhibit the development of **HCC (hepatocellular carcinoma?)** and improve survival
49
What is the most common serotype of HCV in the US?
Genotype I
50
What is the timeline for current treatment of **chronic Hep C**?
**Oral** therapies with direct acting agents from **12-24** **weeks** according to the **genotype (1-4)** of the virus and presence/absence of cirrhosis
51
What is **Imiquimod**?
**Immune response modulator** useful for **topical** treatment of genital warts and several other skin diseases (incl **basal cell** and **actinic keratoses**)
- **TLR7 agonist**
52
What is **fomivirsen**?
**Antisense oligonucleotide** approved for treatment of **CMV retinitis** when other therapies have failed
53
Characteristics of **Telaprevir**?
- Class:
- Mechanism:
- Route:
- Adverse effects:
- Indications:
_- Class_: **NS3/4A protease inhibitor**
_- Mechanism:_ serine protease inhibitor
_- Route_: Oral
_- Adverse effects_: rash, pruritis, anemia, nausea and diarrhea
_- Indications_: **HCV** infection in combination with **IFN and ribavirin**
54
Characteristics of **Boceprevir**?
- Class:
- Mechanism:
- Route:
- Adverse effects:
- Indications:
_- Class_: **NS3/4A protease inhibitor**
_- Mechanism:_ Serine protease inhibitor
_- Route_: Oral
_- Adverse effects_: Anemia, dysgeusia, N, V, D. May increase risk of myopathy in pts on statins
_- Indications_: **HCV** infection in combination with **IFN** and **ribavirin**
55
Characteristics of **Sofosbuvir**?
- Mechanism:
- Route:
- Adverse effects:
- Indications:
_- Mechanism_: **NS 5B "nucleotide" polymerase inhibitor**
_- Route_: Oral (1 pill daily)
_- Adverse effects_: well-tolerated
_Indications_: approved for use for several genotypes:
- **GT 1 or 4**: 12 weeks with IFN/RBV (or alternatively 24 wks with RBV for GT 1)
- **GT 2**: 12 wks with RBV
- **GT3**: 24 wks with RBV
56
Characteristics of **Simeprevir**?
- Class:
- Route:
- Adverse effects:
- Indications:
_- Class_: **NS 3/4 protease inhibitor**
_- Route_: oral (1 pill daily)
_- Adverse effects_: well tolerated, **photosensitivity**, drug-drug interactions with efavirenze, ritonavir/cobi
_- Indications_: **GT 1 only!** (12 wks with extended IFN/RBV with baseline resistance testing before); use with sofosbuvir for 12 wks if no cirrhosis or 24 wks with cirrhosis (no ribavirin, no interferon)
57
Characteristics of **Ombitasvir/paritaprevir/r, dasabuvir (Viekira)**?
- Class:
- Used for:
- Adverse effects:
- Dosing schedule:
_- Class_: **NS 5A, PI/r, NS 5B non-nucleoside polymerase**
_- Used for:_ used **with RBV for GTI** (except in GT 1B without cirrhosis in which case RBV is not needed)
_- Adverse effects_: well tolerated, multiple drug-drug interactions
_- Dosing schedule_: 3 pills in the morning, 1 in evening + RBV if needed
58
Characteristics of **Ledipasivr/sofosbuvir (Harvoni)**
- First ___ regimen approved
- Class:
- Uses:
- Adverse side effects:
- Dosing schedule:
- First **IFN and RBV free** regimen approved
- _Class_: **NS 5A replication complex inhibitor/NS 5B**
- _Uses_: Approved for **GT 1 only** (12 wks with 94-99% cure rates!)
- _Adverse side effects_: well-tolerated; may interact with efavirenz, cobi or ritonavir to elevate TDF levels
- _Dosing schedule_: co-formulated, one pill once daily
59
**Case 1:**
66 y.o. male with COPD presents with a 12 hr history of fever, cough, and myalgias. Local surveillance indicates that both influenza A/H3N2 and influenza B isolates are circulating. A rapid test for influenza is positive. Which one of the following oral medications would be an appropriate treatment choice?
A. Oseltamivir
B. Amantadine
C. Ribavirin
D. Rimantadine
**Case 1:**
66 y.o. male with COPD presents with a 12 hr history of fever, cough, and myalgias. Local surveillance indicates that both influenza A/H3N2 and influenza B isolates are circulating. A rapid test for influenza is positive. Which one of the following oral medications would be an appropriate treatment choice?
A. Oseltamivir
B. Amantadine
C. Ribavirin
D. Rimantadine
60
**Case 2:**
A 6 month old boy with congenital heart disease presents with severe bronchiolitis requiring hospitalization for respiratory support during an RSV epidemic. A rapid test for RSV is positive. Which of the following is the most appropriate approach to therapy?
A. Inhaled zanamivir
B. Intravenous zanamivir
C. Inhaled ribavirin
D. Intravenous ribavirin
**Case 2:**
A 6 month old boy with congenital heart disease presents with severe bronchiolitis requiring hospitalization for respiratory support during an RSV epidemic. A rapid test for RSV is positive. Which of the following is the most appropriate approach to therapy?
A. Inhaled zanamivir
B. Intravenous zanamivir
C. Inhaled ribavirin
D. Intravenous ribavirin
61
**Case 3:**
A healthy 23 year old female presents with diffuse, painful genital ulcerations. Primary HSV2 infection is diagnosed. One year later she reports that lesions reappear each month. Which of the following agents is NOT indicated for suppression of her recurrences?
A. Acyclovir
B. Famciclovir
C. Ganciclovir
D. Valacyclovir
Case 3:
A healthy 23 year old female presents with diffuse, painful genital ulcerations. Primary HSV2 infection is diagnosed. One year later she reports that lesions reappear each month. Which of the following agents is NOT indicated for suppression of her recurrences?
A. Acyclovir
B. Famciclovir
C. Ganciclovir
D. Valacyclovir
62
**Case 4:**
A healthy 16 y.o. presents with varicella. Lesions started 18 hours ago. His 7 y.o. sister had varicella three weeks earlier. Which of the following statements is TRUE?
A. Therapy is not indicated because there is no effective therapy.
B. Therapy is not indicated because it is too late.
C. Therapy is available and may provide benefit.
D. Therapy is available but it is too toxic to use for treatment of varicella in a healthy host.
**Case 4:**
A healthy 16 y.o. presents with varicella. Lesions started 18 hours ago. His 7 y.o. sister had varicella three weeks earlier. Which of the following statements is TRUE?
A. Therapy is not indicated because there is no effective therapy.
B. Therapy is not indicated because it is too late.
C. Therapy is available and may provide benefit.
D. Therapy is available but it is too toxic to use for treatment of varicella in a healthy host.
63
**Case 5:**
A previously healthy 80 year-old presents with painful vesicular lesions in the ophthalmic distribution of the fifth cranial nerve of 24 hours duration; ocular involvement is apparent. HZ is diagnosed. Which one of the following is the most appropriate approach to management?
A. Symptomatic treatment
B. IV Acyclovir therapy
C. Ganciclovir therapy
D. Famciclovir therapy
**Case 5:**
A previously healthy 80 year-old presents with painful vesicular lesions in the ophthalmic distribution of the fifth cranial nerve of 24 hours duration; ocular involvement is apparent. HZ is diagnosed. Which one of the following is the most appropriate approach to management?
A. Symptomatic treatment
B. IV Acyclovir therapy
C. Ganciclovir therapy
D. Famciclovir therapy
64
**Case 6:**
A 40 year old male with advanced HIV infection (CD4 ct \< 50) complains of loss of vision. Ophthalmoscopic exam reveals severe bilateral retinitis. The diagnosis of CMV retinitis is made. Which of the following is not effective and appropriate treatment?
A. Acyclovir
B. Cidofovir
C. Foscarnet
D. Ganciclovir
**Case 6:**
A 40 year old male with advanced HIV infection (CD4 ct \< 50) complains of loss of vision. Ophthalmoscopic exam reveals severe bilateral retinitis. The diagnosis of CMV retinitis is made. Which of the following is not effective and appropriate treatment?
A. Acyclovir
B. Cidofovir
C. Foscarnet
D. Ganciclovir
