What is the main goal of Hep C drug development?
- Want a single, daily pill that is effective across the different genotypes, that will be successful in eradicating Hep C in 4-6 weeks
2. Duration of 4-6 wks
3. Once daily
4. Well tolerated
5. No resistance
What are the problems with INF tx for HBV and HCV?
- 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
What are 2 Tenofovir AE's?
Can be nephrotoxic because accumulates in cells
1. Genetic predisposition due to malfunctioning transport protein —> trapped in the cell
2. MONITOR serum creatinine/BUN, phosphate
- DEC bone density: osteoporosis
What is major concern with Ribavirin?
- Hemolytic anemia (about 10%)
What is the drug list for HBV?
- Adefovir dipivoxil
- Emtricitabine: in HIV/HBV co-infected pts
- Peginterferon alfa-2b and Peginterferon alfa-2b: can also be used to tx HCV
What is the drug list for HCV?
- Previrs (NS3/4A):
- Asvirs (NS5A):
- Buvirs (NS5B):
What are the basics for tx of chronic HBV?
- 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
- 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
What are the 3 classes of orally active HBV antivirals? Why do these matter?
- 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
What are the MOA's of the 5 orally active HBV antivirals? Resistance?
- 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
What is the ADME of the orally active HBV antivirals?
- 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
How does Tenofovir affect the kidney? Monitoring?
- 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
How does Tenofovir impact bone health?
- 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
For what drugs do you need to monitor LFTs? Why?
- 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
What drugs should be used for pts with HBV and HIV co-infection?
- 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
How is HBV/HCV co-infection treated?
- Initially with Peginterferon and Ribavirin to target HCV
What is the MOA of the interferons?
- Endogenous proteins released in response to patho infection -> pleiotropic bio effects, incl antiviral, antiproliferative, and immunomodulatory actions
- Binds cell surface receptor to activate tyrosine kinases, leading to production of several IFN-stimulated enzymes (IFN-stimulated genes, ISG's)
1. Endoribonucleases to cleave ss viral RNA
2. INH effects on dsDNA
- INH of viral penetration and uncoating, and/or viral assembly and release
- Enhanced lytic effects of cytotoxic T lymphos
How is interferon administered? Duration? Minor AE's?
- IM or SC admin
- Cellular effect, exceed persistence of drug in body
1. Pegylation provides sustained serum drug levels, permitting once weekly dosing: straight chain vs. branched chain PEG (2 products)
- Active influenza-like syndrome after injection: fever, chills, headache, myalgia, arthralgia, N/V, diarrhea
1. Pt tolerized to these over time; use anti-pyretics
- Pegylated products usually better tolerated; lower rates of discontinuance
What are the major interferon AE's?
- Neuropsych issues (BBW): depression (higher in HCV than HBV), somnolence, confusion, behavioral changes, and rarely, seizures (effect on serotonin or corticotropin?)
- Granulocytopenia and thrombocytopenia
- INC hepatic enzymes, TG's: hepatotoxicity possible
1. Monitor thyroid func and hepatic enzymes during therapy -> immune-mediated destruction of thyroid tissue in genetically predisposed; may produce temp THYROTOXICOSIS (wks-mos)
- Infrequent devo of serum neutralizing Ab's, causing loss of clinical responsiveness (uncommon)
What are the MOA's of Ribavirin? Synergism?
- MOA's: enhance T-cell immune clearance of HCV
1. INH of host inosine monophosphate de-hydro (IMPDH), w/depletion of pools of guanosine triphosphate, essential viral RNA syn substrate
2. Direct INH of HCV replication: RNA-dep RNA poly
3. RNA virus mutagenesis that drives HCV to error catastrophe
- May only transiently DEC HCV RNA levels, but often normalizes serum ALT
- Synergizes w/INF, greatly enhancing activity: DEC risk of viral relapse, and still a crucial tx component
What are the ADME and toxicity of Ribavirin?
- Bioavailability: INC by high fat meal
- Extensive uptake into cells, incl. erythrocytes: very large vol of distribution (Vd) + long half-life (twice daily dosing)
- No CYP axn; renal elim -> accumulation possible
- 1o toxicity is HEMOLYTIC ANEMIA (10-13%): w/in 1-2 wks of initiation of tx -> monitor Hct pre-tx, 2, & 4 wks
1. Fatal and non-fatal MI and difficulty breathing reported, 2o to ribavirin-induced anemia
- Dose adjustments may be required
What 2 drugs have INC bioavailability with high fat meal?
What 3 drugs exhibit male-mediated teratogenicity?
- Ribavirin, Bocepravir, Telaprevir (2nd 2 are guilty by association b/c they must be used with Ribavirin): teratogenic and embryocidal in animals
- CONTRAINDICATED in: 1) women in pregnancy, 2) women who could become pregnant, 3) men whose partners are pregnant
- Women of repro age w/HCV should be advised to use 2 forms of contraception during tx, and at least 6 mos following end of tx
What 3 proteins are INH by HCV drugs? Where?
- Membrane of the endoplasmic reticulum (ER)
- NS3/4A INH: previr
- NS5A INH: asvir
- NS5B INH: buvir
What is the role in viral replication of the proteins INH by HCV drugs?
- Non-structural, but involved in some aspect of post-translational processing of HCV polyprotein
- These drugs do NOT prevent transcriptase activity, but rather they prevent protein maturation
- NS3A/NS4A: protease -> 1st and 2nd-gen INH
1. Upon being cleaved by host and viral peptidases, these proteins assemble together and cleave the downstream proteins, including NS5A-NS5B
How can HCV rapidly develop resistance to tx?
- Poor proofreading by HCV RNA poly and rapid turnover of circulating virions means a complex mix of different HCV variants/quasi-species exists
- Drug tx may influence emergence of resistant strains that arise from pre-existing sub-populations as wild-type virus is cleared
What are the 1st-gen protease INH? AE's?
- Telaprevir and Boceprevir: high potency oral drugs taken 3x daily w/Peginterferon and Ribavirin
- Comparable effectiveness vs. genotype 1; benefit in naive pts and those relapsing on combo tx
- AE's: nausea and diarrhea, fatigue and anemia
1. Telaprevir (not Boc) assoc w/pruritis, rash; may be serious (BBW) -> DRESS, SJS, TEN, EM
- Potential for teratogenicity: male and female
What are the 2nd-gen protease INH? How are they different from the 1st-gen drugs?
- Semeprevir and Paritaprevir: improved activity vs. genotypes 1, 2, 4, 5, and 6
- ONCE-DAILY DOSING
- Improved safety profile: fatigue, photosensitivity, rash, and GI toxicity remain a problem
- Continued devo aimed at improving activity against genotype 3
What is the role of NS5A and NS5B in HCV replication? Drugs?
- NS5B: polymerase whose INH leads to interrupted HCV replication
1. Sofosbuvir, Dasabuvir
- NS5A: function unknown, but drugs that bind to this protein also prevents viral replication (biphasic effects suggest 2 MOA's)
1. Pan-genotypic action: highly conserved drug binding site -> resistance can devo, but useful in drug combos (generally well tolerated)
2. Daily dosing (long 1/2-life); possibility of CYP interactions
3. Daclatasvir, Ledipasvir, Ombitasvir
What is the polymerase catalytic INH? Drug basics?
- SOFOSBUVIR: requires 3 phosphorylation to active (nucleoside INH) analog of natural substrate -> highly conserved catalytic site (-tides: 2 phosphorylation)
1. Initial phosphorylation step can be rate-limiting (governs speed of onset of action)
- Pan-genotypic activity, and emergence of resistant strain uncommon
- Interactions possible via P-gp: concurrent INH of P-gp (drug or food) can INC bioavailability of these Rx
- Generally well tolerated: fatigue and headache are common AE's
What is the polymerase allosteric INH? Drug basics?
- DASABAVIR: 4 allosteric drug binding sites; binding results in enzyme conformation change
- Sites less conserved than catalytic; variable across genotypes -> active predominantly against 1a/1b
- Low barrier to resistance, but not cross-resistant to outcomes w/other drug classes
- Useful in combo tx, and generally well-tolerated: fatigue, dermal and GI toxicity are common AE's
- Interaxns w/P-gp and CYP2C8 possible
For which class of drugs should you be most concerned about drug-drug interactions?
- Direct-acting antivirals (DAA's) for HCV: all handled by hepatic processes
- Potential for P-gp and CYP interaction w/concurrent meds must ALWAYS be considered
1. Databases exist to provide guidance
What is the current staple of HCV tx?
- Nucleotide INH are backbone of tx, based on:
1. High potency, pangenotypic action, and lack of resistance
2. Combined w/other DAA's in single combo pill for better adherence: Harvoni, Viekira-Pak
a. May contain Ritonavir for a "boost" b/c INH CYP3A4 and 2D6 -> extends drug persistence, or remove need for compensatory dose escalation
b. Combo can also extend drug activity or diminish significance of drug resistance