Sweatman - Drugs for HCV/HBV Flashcards
1
Q
What is the main goal of Hep C drug development?
A
- Want a single, daily pill that is effective across the different genotypes, that will be successful in eradicating Hep C in 4-6 weeks
1. Pangenotypic
2. Duration of 4-6 wks
3. Once daily
4. Well tolerated
5. No resistance
2
Q
What are the problems with INF tx for HBV and HCV?
A
- Parenteral admin
- Side effects:
1. Modulates immune system, which damages liver: AE can be liver enzyme changes
2. Neuropsych issue is a BBW: must immediately terminate tx if this arises in pt
3
Q
What are 2 Tenofovir AE’s?
A
Can be nephrotoxic because accumulates in cells
- Genetic predisposition due to malfunctioning transport protein —> trapped in the cell
- MONITOR serum creatinine/BUN, phosphate
- DEC bone density: osteoporosis
4
Q
What is major concern with Ribavirin?
A
- Hemolytic anemia (about 10%)
5
Q
What is the drug list for HBV?
A
- Tenofovir
- Entecavir
- Telbivudine
- Adefovir dipivoxil
- Lamivudine
- Emtricitabine: in HIV/HBV co-infected pts
- Peginterferon alfa-2b and Peginterferon alfa-2b: can also be used to tx HCV
6
Q
What is the drug list for HCV?
A
- Ribavirin
- Previrs (NS3/4A):
1. Telaprevir
2. Boceprevir
3. Simeprevir
4. Paritaprevir - Asvirs (NS5A):
1. Ledipasavir
2. Ombitasvir
3. Daclatasvir - Buvirs (NS5B):
1. Sofosbuvir
2. Dasabuvir
7
Q
What are the basics for tx of chronic HBV?
A
- 5 orally active antivirals are front-line therapy: better tolerated than interferons and better suppression of the virus
- Tenofovir or Entecavir preferred
- Alternative regimens may be preferred due to:
1. Resistance (and prior drug history)
2. Comorbid disease
3. Co-infection - Combo regimens may diminish resistance devo, but are not necessarily more effective
1. Emergence of resistance likely the outgrowth of a pre-existing clone following the eradication of the drug sensitive viral populations
8
Q
What are the 3 classes of orally active HBV antivirals? Why do these matter?
A
- L-nucleosides: Lamivudine, Telbivudine
- Acyclic phosphonates: Adefovir, Tenofovir disoproxil fumarate
- D-cyclopentane: Entecavir
- While the class names are not important, antiviral drug resistance tends to be structure (sugar residue) specific -> potential issues of cross-resistance
1. Arises from muts in HBV polymerase
9
Q
What are the MOA’s of the 5 orally active HBV antivirals? Resistance?
A
-
Tenofovir disoproxil: pro-drug for Tenofovir, a nucleoside analog of adenosine-5-monophosphate; disphosphonate form INH HBV poly/produces chain termination
1. Adefovir: adenosine-5-monophosphate; disphosphonate form INH HBV poly/produces chain termination - Entecavir: guanosine nucleoside analog; triphosphate form INH HBV poly
-
Lamivudine/Emtricitabine: L-isomers of cytosine w/similar activity, potency, side effects, and patterns of resistance; triphosphate form INH HBV poly
1. Telbivudine: L-isomer of thymidine; triphos-phonate form INH HBV poly/causes chain term - Resistance arises from muts in viral enzyme, leading to DEC drug binding affinity; may extend to some other drugs, but not all the different structural classes, so doc can plan for “follow-up” drug
10
Q
What is the ADME of the orally active HBV antivirals?
A
- Adefovir dipivoxil and Tenofovir are pro-drugs that rapidly liberate active species -> INC bioavailability
- Orally active drugs (counsel pt on how to take):
1. Food delays absorption of Entecavir
2. High fat meal INC bioavailability of Tenofovir - 1/2 life ranging from 7hr (Lam) to 130 hrs (Entecavir), so take once daily
- NO CYP interactions of note
-
Urine elim by passive +/- active mechs: drug-drug interaxns possible via competitive renal secretion
1. Dose reduction may be required w/renal dysfunction, e.g., elderly
11
Q
How does Tenofovir affect the kidney? Monitoring?
A
- Acute renal failure (ARF), most often in pts with:
1. Systemic/renal disease or concurrent nephrotoxic drugs (like NSAIDs)
2. Sometimes in pts w/NO identified risk factors
3. Possible extraordinary accumulation in prox tubule cells due to (genetic) active transporter protein absence or dysfunction - Serum creatinine/BUN and phosphate testing recommended -> also recommended for Lamivudine, Adefovir, and Entecavir
- Ask pt about persistent or worsening bone pain, pain in extremities, bone fxs, muscle pain/weakness b/c may be manifestations of prox renal tubulopathy
12
Q
How does Tenofovir impact bone health?
A
- Antiretrovirals produce DEC bone mineral density and INC markers of bone turnover
1. INC risk of osteoporotic fracture - Likelihood: Tenofovir > Stavudine or Abacavir
- Ca and Vit. D supplements recommended in tx of HIV
13
Q
For what drugs do you need to monitor LFTs? Why?
A
- MONITOR for: Adefovir, Telbivudine, and Entecavir
-
Lactic acidosis, steatosis w/nucleoside/nucleotide analog antiretrovirals
1. NRTI’s INH mito DNA poly gamma, which is essential for mito DNA replication and energy-producing capacity - Most often in women; obesity, alcoholism, and prolonged drug exposure may also be risk factors
- Suspend tx in any pt who devos findings suggestive of lactic acidosis or pronounced hepatotoxicity (incl. hepatomegaly and steatosis), even in absence of marked transaminase elevations, which is the common presentation
14
Q
What drugs should be used for pts with HBV and HIV co-infection?
A
- Tenofovir: active against both
- Entecavir: weakly active against HIV, but can induce M184V variant, which is resistant to Lam and Emtri
- Emtricitabine: approved only for HIV, but produces histo, virologic, and biochem evidence of activity against HBV -> useful in co-infected pts
- Tenofovir and Emtricitabine more effective than other regimens: available in fixed dose (Truvada)
- Don’t use Lam and Emtri b/c structurally similar, and would offer no advantage
15
Q
How is HBV/HCV co-infection treated?
A
- Initially with Peginterferon and Ribavirin to target HCV
23
Q
What 3 proteins are INH by HCV drugs? Where?
A
- Membrane of the endoplasmic reticulum (ER)
- NS3/4A INH: previr
- NS5A INH: asvir
- NS5B INH: buvir
