How does HBV replicate?
Hep B is a pararetrovirus, that is, it is a non-retrovirus that uses reverse transcriptase in their replicative process. The virus gains entry into the cell by binding to NTCP on the surface and being endocytosed. After viral uncoating, the nucleocapsid moves to the nucleus via host chaperones where the virion DNA polymerase synthesizes the missing portion of DNA, and a ds circular DNA is formed.
The DNA then serves as a template for individual mRNA synthesis by cellular RNA polymerase. After the individual mRNAs are made, a full-length positive-strand RNA in made, which is the template for the minus strand of the progeny DNA. The minus strand then serves as the template for the plus strand of the genome DNA. This RNA-dependenat DNA synthesis catalyzed by reverse transcriptase encoded by HBV takes place within the newly assembled virion nucleocapsid in the cytoplasm
Progeny HBV with its HBsAg-containing envelope are released by budding
How does HCV replicate?
It replicates in the hepatocytes of the liver via the following steps:
1) HCV binding
2) Entry via receptor-mediated endocytosis
3) uncoating of viral RNA and viral RNA translation in the rough ER
4) formation of a replication complex in the vesicular membrane structures to catalyze the amplification of the positive-strand RNA genoma
5) Maturation and release of virions
What are the drugs available for Rx of Chronic hepatitis B?
What are the drugs available for Rx of Chronic Hepatitis C?
Boceprevir, Grasoprevir, Paritaprevir, Simeprevir, Telaprevir
Daclatasvir, Ledipasvir, Ombitasvir, Valpatasvir
What are the drugs available for Rx of both Chronic Hepatitis B and C?
peginterferon alfa 2b (Intron A) and 2a (Pegasys)
"-previrs" act on _____
"-asvirs" act on _____
"-buvirs" act on _____
Describe the tx of chronic HBV
The 5 orally active antivirals are front-line (better tolerated than interferons, easier for outpt., and show better viral supression). Currently, Tenofovir and Entecavir are preferred with alternative regimens being used mostly in cases of resistance, comorbidities, and co-infection.
Note that combination regiments may diminish resistance development but are not necessarily more effective
What oral HBV drugs are part of the L-nucleoside family? acyclic phosphonates? d-cyclopentanes?
L-neucleosides: Lamivudine and Telivudine
Acyclic phosphonates: Adefovir and Tenofvori disoproxil fumarate (TDF)
Antivrial resistance tends to be structure specific
T or F. Oral HBV drugs are false DNA building blocks
T. Causing viral DNA strand termination and inhibiton of polymerase. In general, these drugs require phosphorylation prior to incorporation into the DNA production cycle
How does Tenofovir disopoxil work?
pro-drug for Tenofovir a nucleoside analgos of adenosine-5-monophosphate/ The diphosphate form inhibits HBV polymerase and produces chain termination
How do entecavir, lamivudine, and emtricitabine work?
Entecavir: guanosine nucleoside analog
Lamivudine and Emtricitabine are L-isomers of ytosine with similar activity, potency, side effects, and patterns of resistance
NOTE: The triphosphate form of all of these inhibit HBV polymerase and produce chian termination
Describe the ADME of the orally active HBV drugs
-Adefovir disoproxil and tenofovir are pro-drugs
Food delays absorption of entecavir and high fat meals increase the bioavailability of tenofovir
-no significant CYP interactions
-all eliminated in urine (drug reduction with renal dysfunction)
What is a noticeable AE of tenofovir?
ARF, most often in pts with:
-systemic/renal disease or concurrent nephrotoxic drugs but can be in those with no risk factors
-possible accumulation in proximal tubule cells due to genetic active transporter protein absence of dysfunction
How should tenofovir be monitored?
-serum creatinine/BUN and phopshate testing recommended (also recommended in lamivudine, adefovir, and entecavir)
-avoid concurrent nephrotoxic agents like NSAIDs
-ask pt about worsening bone pain/fractures as they may suggest tubulopathy
T or F. Antiretroviral drugs have been shown to decrease bone density
T. Tenofovir is worse than stavudine or abacavir
Calcium and vitD supplements are recommended in the tx of HIV
What is another potential toxicity of oral HBV drugs?
T or F. LFTs are recommended for adefovir, telbivudine, and entecavir
What viruses is Tenofovir active against?
HIV and HBV
other HBV drugs active against HIV: Entecavir (weakly- can induce M184V strain), Emtricitabine.
Dont ever give lamivudine AND emtricibine at the same time (same structure)
What is the best drug for co-infection of HBV and HIV?
Truvada (Tenofovir and Emtricitabine)
How would HBV/HCV co-infection be tx?
initially with peginterferon and ribavirin to target the HCV
How do interferon drugs work?
They bind to cell surface receptors to activate tyrosine kinases, which leads to the production of several IFN-stimulated enzymes
-endoribonucleases to cleave single-stranded viral RNA
-inhibitory effects upon ds RNA
-inhibition of viral penetration and uncoating, and/or viral assembly and release
-enhanced lytic effects of cytotoxic T cells
How are interferon drugs given?
IM or SC
How are interferon drugs formulated today?
mostly as a peg form whos cellular effects exceed the persistence of the drug in the body (allows for 1x/week dosing)
What are the AEs of interferon drugs?
-acute flu like syndrome with injection (fever, chills, HA, myalgia, etc.)
-neuropsychiatric issues (depression, somnolence, confusion, and rarely seizures)
-granulocytopenia and thrombocytopenia
-elevated hepatic enzymes and TAGs
-developing of serum neutralizing Abs rarely
What monitoring should be done on a pt taking an interferon?
-thyroid function (immune-mediated destruction of thyroid tissue can cause temporary thyrotoxicosis), hepatic enzymes, mental state,
T or F. Tx of chronic HCV requires genotpying the pts. infection becuase drug choice is predicted upon the target options
T. There are 7 genotpyes (GT 1 most common)
Changing landscape for HCV
Some oral regimens for HCV infection
How is ribavirin used in HCV tx?
It is proposed to work by enhancing host T-cell clearance, inhibiting host inosine monophosphate dehydrogenase (IMPDH), with depletion of guanosine triphosphate, as essential substrate for vial RNA synthesis (i.e. inhibits viral replication by the triphosphate form)
It also inhibits RNA-dependent RNA polymerase