3. HB Therapeutics Flashcards
Normal > chronic hepatitis w/ ____ > cirrhosis»_space;
Decomp cirrhosis
- ____
- hepatic encephalopathy
- variceal ____
OR
____
> >
liver transplant
fibrosis
ascites
bleeding
HCC
HCV- Viral life cycle
• Evnvelope \_\_\_\_ virus ○ Intiially found incidentally, but then mech of rep was figured out > breaktkthrough in therapeutics ○ Virus binds reeptors hepato > viral enveolpe > relaese viral capsid protein > contains viral genome > polyprotein > broken down into indiviudal compoentn s> protease activity ○ **component of the virl polyportien > \_\_\_\_; the host cell will not have an RNAdependent polymerase § In order to rplicated viral genome need \_\_\_\_ > viral genoe is replicated > genoe and stuctural components are rpelciated
ss RNA
viral polymerase
viral polymerase
HCV genotypes
• Viral replication rate is very ____: 1012 virions /day
• The viral RNA-dep RNA polymerase lacks ____ activity
High ____ rate
• Clusters of HCV with sequence similarities >60% remain ____ within the individual patient: “genotype”
* High mutation rate > how the virus evades the immune response * Virus within an patient tht has a sequence that's protected from the mutation rate in the viral genotype > remains constant
elevated
proofreading
mutation
constant
HCV Genotypes in the US • - \_\_\_\_ ~ 75% - Genotype 2 ~ 15% - Genotype 3 ~ 7% - Genotype 4, 5, 6 < 5% • Clinical significance of HCV genotypes: - No impact on the \_\_\_\_ of liver injury - Major impact on the likelihood of \_\_\_\_ to HCV therapy
• 6 genotypes ○ 1,2 3 are most common in the US ○ 456 common in other parts • Genotype has impact on which drug you will use ○ The viral compositino may differ among genotypes
genotype 1
severity
response
Chronic Hepatitis C – Natural History
• Majority of patients w HCV > chonic infection > \_\_\_\_ in 20%; once develops > 5%/ear dev \_\_\_\_ or decomp cirrhosis
cirrhosis
HCC
Gold standard for response to HCV treatment: Sustained Viral Response (SVR)
- Defined as the absence of detectable ____ in blood ____ wks (SVR 24) or ____ wks (SVR 12) after the end of the course of therapy
- < 1% chance of detecting HCV after ____• How to measure success of treating HCV
• SVR
○ Absence of detectable HCV after therapy
○ Can be in 12 or 24 weeks
○ Important: important virological endpoint
§ Achieve the response milestone > cahnce of ever seeing the virus again in blood is <1% > ____ of virus
HCV
24
12
SVR
erradication
Effect of SVR on patients with advanced fibrosis/cirrhosis
• Not just virological endpoint, orrelates in reduction in risk of complications as well (clinically!) • Sutyd of patiets who were treated ○ Patients who respond w SVR > lower \_\_\_\_ over long term follow up ○ Liver specific mortality is even bigger; mortality is driven by liver disease so it's low ○ Patients were selected who were undegroing cirrhosis ○ Don't treat successfully > risk of dying from liver dx at 10 years > \_\_\_\_% • SVR is important bc it prevents serious \_\_\_\_ of iver dsisae ○ Prevent \_\_\_\_ of dx down spectrum, and prvenets liver cancer and failure
mortality
20-22
complications
progression
General Principles in HCV Treatment
* Expose pt to a drug > produce a response > \_\_\_\_ level drops * Then continue to treat beyond the \_\_\_\_ where virus isn't detected > virus is mostly in liver > treat for longer than the time where the virus isn't in blood > clear the resoirvori from the \_\_\_\_ (\_\_\_\_ treatment) > then stop > virus load 10-24 weeks later > is the response sustained?
virus
phase
liver
maintenance
Interferon and Ribavirin in hepatitis C treatment (1990s to 2011)
• Interferon (IFN) is a ____ that activates the anti-viral immune response
• Ribavirin (RBV) is a ____ analogue that inhibits viral replication
• (____) x 6-12 mos was the first treatment for HCV:
- Limited efficacy (~50% SVR in geno 1)
- Many ____
• First xtnebt available > interferon > cytokine ○ \_\_\_\_ injections ○ Activates antiviral immune response • Combination of the two were tested in anumber of infections ○ Soe patients got an improvement in liver tests • Problem: needed xment that was injection based for 6-12 mo > even in patients who could \_\_\_\_ (a lot of SE from the cytokines) > the chance of an SVR was only 50% in the ost common genotype (1)
cytokine
guanosine
IFN+RBV
side effects
tolerate
HCV - viral life cycle
• Treamtnet was dveloepd before we knew how the virus replicated • Was based on non-specific replication of virus • Can now target specific areas to prevent the replication of virus ○ Three targets: § \_\_\_\_ (NST34A) § NS5B (\_\_\_\_) § \_\_\_\_ (helps in the viral replciation) § Inhibit any > virus cannot replicated
viral protease
viral dependent RNA polymerase
helicase
The new era in HCV therapy: Directly Acting Antivirals
• Development of new drugs in HCV therapy targeting specific components of the ____
• Goals :
1. Improving ____
2. Reducing adverse effects of ____ therapy
viral replication cycle
SVR
HCV
Conceptual Evolution of Mutations on Monotherapy
• Cannot use as \_\_\_\_ > virus has high mutation rate > develop resistant mutants • Drugs that are specific to one component > have to use them in \_\_\_\_ ○ At east \_\_\_\_ steps in order to not develop mutations
monotherapy
combination
two
• Don’t need to know • Target at least two components of viral rep process • Viral protease inhib have easy identifier ○ -\_\_\_\_ • NS5B inhibit ○ -\_\_\_\_ • Viral polymerase inhib ○ -\_\_\_\_
previr
asvir
buvir
Current HCV treatment
• All ____
~ 90- 95% chance of SVR with 1st line
~ Vast majority of failures to first line therapy can be treated ____ with second line agents
- Treatment well tolerated with little adverse effects
• Likelihood of clearing HCV has gotten so good ○ 90-95% success rate w oral drugs and little SE • Patients who fail first line therapy > have second line therapy that will clear the virus • No patient w HCV that you cannot treat properly
genotypes
successfully
Remaining challenges in HCV therapy
• ____ patients with HCV
• ____ of decompensated cirrhosis
• ____ of therapy / access to care
• Silent infection until they develop serious complications ○ Screening anyone bron bt 45-65 > 80% of infected patients in the US § \_\_\_\_ epidemics > new wave of HCV infections • Treat pt w decomp cirrhosis > cannot get them recompensated ○ Too late to prevent from iver transplant • Cost of therapy is getting better ○ Inusrance had a hard time covering high cost of therapy
identifying
reversibility
cost
opiates
Virology • \_\_\_\_ family • 44 nm virion: - Host-derived lipoprotein envelope expressing \_\_\_\_ - \_\_\_\_ protein (HB core Ag) - \_\_\_\_ - Partially ds \_\_\_\_
* HBV has a vaccine bc of a neutralizing ab * DNA virus * Virological diff bt HCV and HBV > big diff in treatment
hepadnaviridae HBsurfaceAg core capsid DNA polymerase DNA
HBV Replication
• HBV is DNA virus that has ability to target nucleus of cell where it's used as repair machinery > closed circuarl DNA > genomic form of virus that \_\_\_\_ in cell for as long as its alive • All targets are at the \_\_\_\_ which is needed for replication ○ None of them target the stable \_\_\_\_ form ○ C is an RNA virus > cytoplasm of cell > desn't rep it's gone ○ B can sit and not replciated and persist for a long tiem
survive
viral polymerase
DNA
Immune Response to HBV
Replication of the virus does little direct damage to ____
The hepatic injury is mostly due to the ____ to the virus
The degree of immune tolerance to ____ will determine whether a chronic infection will develop (HBsAg positive > 6 months)
• The rep of the virus can induce an immune response > results in tissue injury • Most patients exposed to HBV as adult > clear the \_\_\_\_ ○ The hepatitis > the symptoms > function of immune response to virus ○ Children w underdeveloped immune > less likely to clear, and less likely to get \_\_\_\_ § All depends on the immune response!
hepatocytes immune response hepatitis B virus sick
Key Hepatitis B tests and their significance
• ____: indicates the presence of the virus in an individual
• ____: indicates immunity to the virus, acquired by vaccination or naturally by immune clearance
• ____: core antibody persists in any individual exposed to the virus (current or past infection)
• ____: e-antigen secreted with active replication of the ‘wild-type’ virus
• ____: antibody to eAg becomes positive when eAg titers decrease
• ____: presence of viral DNA in the blood
• HBsAb > neutralizing ab • WT virus secretes e antigen > virus is actively replicating ○ If e antigen goes down, the antibody will appear ○ Immune complex phenomenon § Both are typically present; but no replication you will detect ab, and vice-versa
HBsAg HBsAb HBcAb HBeAg HBeAb HBV DNA
Phases of Chronic Hepatitis B
• Role of immune system in rlationship to hepB infection • Acquire inf perinatally (mother to child) > immune system of the infant is \_\_\_\_ > tolerates the viral inf > high levels of \_\_\_\_, normal ALT (immune system isn't attacking) Eant \_\_\_\_ and Eab - • Adults acquire acute inf > most clear bc of the \_\_\_\_ > if don't > chronic hepatitis > ongoing immune respnose but not clearing it > high \_\_\_\_, high DNA, Eant \_\_\_\_ (eant+ chronic hep b) • Some patients, bc itnerplay w immue system > atsome point it controls replciation > low or undet DNA > Eant \_\_\_\_ and Eab + > ALT normal ○ Inactive carriers for HepB • Can hav virus develop mutation > replciate w/o \_\_\_\_ (core mutantI9 > not as effective at rep as WT (not as high DNA), there is an immune response > ALT is high, but cannot control ○ Eant-chronci hepB • L is youngr; R is older • Virus can persist for decades, over the history of dx > you have the whole spectrum • Stages are not \_\_\_\_, can go from one to the other • Hard time clearing the virus > hard time making them surface ant negative bc of the stable genomic form of virus > persist • Good at prveenting viral rep and preventing liver injury ○ Turning everyoe into an ainactive carrier, that's what we want
immature
DNA
+
immune response
ALT
+
-
Eant
static
Indications for HBV treatment
• Elevated ____
• Elevated ____
• Patients with cirrhosis and any detectable HBV DNA
• Don’t treat \_\_\_\_ carriers, bc all treatment is bc of target rep • ALT > injury • If having cirrhosis, even if ALT is not elevated> ptwent torugh cycles of swithces bt phases several times ○ Can look inactive, but not really that ○ Liver damage in these patients • Cirrhosis, any detectable virus > reason to treat
ALT
HBV DNA
inactive
Endpoints of chronic hepatitis B therapy
• ____ seroconversion (in eAg + patients)
• HBV viral DNA ____
• Normalization of ALT
• Improvement in ____ and fibrosis on liver histology
• ____ loss: rarely achieved
• W C it's SVR • HBV ○ Doesn't happen, rarely ever lose the surface antigen • eAg + > make them - • Try to bring the DNA down • Patients who respond well > lower number of red box > less LF, less decomp, less ascites, less encephalopathy and HCC
eAg
suppression
inflammation
HBsAg
Pharamcological agents for chronic hepatitis B
• \_\_\_\_ • Telvibudine • \_\_\_\_ • Adefovir • \_\_\_\_ - Viral polymerase inhibitors Oral agents
• Pegylated interferon alpha 2a
• All are viral pol inhibit • Entecavir and tenofovir ○ Used most often ○ They are the most potent ○ Trying to suppress viral replication > target one comp of the virus > must suppress it hard § Most potent = lowest \_\_\_\_ risk § Allowing virus to replicate in presence of drug > tends to casue mutations • Pegylated interferon ○ Option for HBV ○ \_\_\_\_ antiviral effect ○ Used when oral drugs were not as effective
lamivudine
entecavir
tenofovir
mutation
nonspecific
Treatment of eAg positive chronic HBV
• Goal: ____ seroconversion (eAg negative, eAb positive)
• Oral agents: 20 - 50% (increased with longer duration of therapy)
• Pegylated Interferon for ____ months: 30%
eAg
12
Treatment of eAg negative chronic HBV • Goal: Long term \_\_\_\_ suppression • Oral agents: 50-90% • PEGIFN: 20% • eAg negative patients have a high \_\_\_\_ rate off therapy: PEGIFN is generally avoided
DNA
relapse
Alcohol-mediated liver injury
• Alcohol-mediated liver injury results in ____ accumulation: increased synthesis and inhibition of fat export from the liver
• Oxidative stress within the liver due to depletion of ____
• Immune response to altered cellular proteins results in liver ____ and fibrosis
• The alcohol injury > inc fat synthesis ○ Typical > hepatic steatosis is the common injury ○ Most common > \_\_\_\_ fatty liver > obesity, diabetes, etc. • Glutathione ○ Used in alcohol metabolism • Steatosis > presence of fat • Steahepatitis > fat and an \_\_\_\_ response from altered proteins due to alc exposure • Can be on either end of things dpeneding on the amount of alcohol drank
fat glutathione inflammation non-alcoholic inflam
Threshold of alcohol intake for alcoholic liver disease
• ____ drinks per week for women
• ____ drinks per week for men
• Based on epi studies looking at the risk of liver injury in people self-reporting their drink ○ Can be an underestimate of what it actually is • No increased risk when drink less than this when compared to non-drinkers • \_\_\_\_ oz of beer, 5 oz of wine, \_\_\_\_ oz for liquor
7
14
12
1.5-2
Clinical manifestations of alcoholic liver disease • Alcoholic Fatty Liver * asyx, \_\_\_\_,liver test mildly abnl * present in 90% of heavy \_\_\_\_ * \_\_\_\_ with discontinuation
• Alcoholic Hepatitis
* acute on chronic liver injury with moderate to severe liver test abnl
* signs of liver dysfunction, liver failure
May be life threatening
• Alcoholic Cirrhosis
Manifests with complications of decompensated ____
• Number of ways where ALD ○ Simplest > AFL § Biopsy > \_\_\_\_ (less inflam) § Asymptomatic § Fat acum > liver larger > hepatomegaly § \_\_\_\_ manifestation of drinking too much • AH ○ Chronic liver injury > acute on chronic injury § Liver test can be mild or sever ○ In the sever form: liver dysfxn and failure > can be life threatening • AC ○ Chronic manifestations ○ Without an \_\_\_\_ component
hepatomegaly
drinkers
reversible
cirrhosis
steatosis
earliest
acute
