Transcript Interferonlambda and therapy for chronic hepatitis C virus infection

Interferonlambda and therapy for
chronic hepatitis C virus infection
Hepatitis is a medical condition defined by
1.the inflammation of the liver and
2.the presence of inflammatory cells in the
tissue of the organ.
 The condition can be self-limiting (healing on
its own) or can progress to fibrosis (scarring)
and cirrhosis.
Hepatitis may occur with limited or no
symptoms, but often leads to
jaundice, anorexia and malaise.
 Hepatitis is acute when it lasts less than six
months and chronic when it persists longer.
Signs and symptoms
Acute
Initial features are of nonspecific flu-like symptoms,
common to almost all acute viral infections and may
include malaise, muscle and joint aches, fever, nausea
or vomiting, diarrhea, and headache.
More specific symptoms are: profound loss of appetite
,dark urine, yellowing of the eyes and skin (i.e.,
jaundice) and abdominal discomfort.
Physical findings are usually minimal lymphadenopathy
(enlarged lymph nodes, in 5%) or splenomegaly
(enlargement of the spleen, in 5%).
• Acute viral hepatitis is more likely to be
asymptomatic in younger people.
Symptomatic individuals may present after
convalescent stage of 7 to 10 days.
• A small proportion of people with acute hepatitis
progress to acute liver failure, in which the liver is
unable to clear harmful substances from the
circulation and produce blood proteins (leading
to peripheral edema and bleeding). This may
become life-threatening and occasionally requires
a liver transplant.
Chronic
• Chronic hepatitis often leads to nonspecific
symptoms such as malaise, tiredness and
weakness, and often leads to no symptoms at
all.
It is commonly identified on blood tests. The
occurrence of jaundice indicates advanced
liver damage.
• Extensive damage and scarring of liver (i.e. cirrhosis) leads to weight loss,
easy bruising and bleeding tendencies, peripheral edema and
accumulation of ascites.
•
Eventually, cirrhosis may lead to various complications: esophageal
varices , hepatic encephalopathy (confusion and coma) and
hepatorenal syndrome (kidney dysfunction).
Causes
Acute
Viral hepatitis:
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Hepatitis A, B, C, D, and E.
Yellow fever
adenoviruses
Parvovirus B19
 Auto immune conditions, e.g.,
systemic lupus erythematosus
(SLE)
 Chronic
 Viral hepatitis: Hepatitis B
with or without hepatitis D,
hepatitis C (neither
hepatitis A nor hepatitis E
causes chronic hepatitis)
 Autoimmune
◦ Autoimmune hepatitis
 Alcohol
 Drugs
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methyldopa
nitrofurantoin
isoniazid
ketoconazole
• Autoimmune
• Anomalous presentation of human leukocyte
antigen (HLA) class II on the surface of
hepatocytes, possibly due to genetic
predisposition or acute liver infection; causes
a cell-mediated immune response against the
body's own liver, resulting in autoimmune
hepatitis.
treatment
Some types of hepatitis, such as acute viral
forms like hepatitis A and sometimes hepatitis
B are self-limited diseases which means that
your body's immune system will eventually be
able to destroy the viruses that caused the
disease.
Goals of Antiviral Therapy
that reduce HBV replication are expected to
limit progressive liver disease and improve the
natural history of chronic HBV infection.
• Doctors often combine different antiviral
drugs to better combat the virus. For example,
interferon treatment may often be combined
with other antiviral drugs like Lamivudine in
the case of hepatitis B infection or Ribavirin
for people with hepatitis C infection.
• The drug combinations have a stronger
therapeutic effect than a singular drug on its
own.
• other antiviral drugs ,Similar to interferon, the
side effects can be severe. However, the costs
of this combination therapy are relatively
reasonable.
Liver Transplantation
• Sometimes hepatitis has developed into such
a serious disease that a liver transplant is the
only treatment left. This is a complex surgical
procedure that involves replacing a failing liver
with a donor liver. Thousands of these
operations are done every year but because
there are many risks involved, it is a treatment of
last resort.
Hepatitis C Treatment
• Currently, taking a combination of two drugs,
peginterferon and ribavirin, is the standard
treatment for chronic hepatitis C.
• This therapy, though not perfect, has the best
record of success in reaching SVR among all
the drugs known to treat the virus.
• Since these drugs work to stimulate your
immune system to fight the virus, some
people have better results from them than
others do.
 SVR is the closest you'll get to "a cure" for
hepatitis. Sustained virologic response, or SVR, is
the goal of hepatitis C treatment.
Conventional treatment (a combination of
interferon and ribavirin) doesn't necessarily
eliminate the hepatitis C virus from your liver.
It can, however, suppress the virus to
undetectable levels for an extended period of
time.
 In clinical language, this is called a "sustained
virologic response," or sustained response. It
means that during the six months after you
complete treatment, there is no detectable
Treatment by interferon
Interferon (IFN) subtypes
• IFNs are characterized in large part by their
ability to induce antiviral activity in receptorbearing target cells.
• IFNs are divided into type I, II and III subtypes,
based in part on the differential use of unique
receptors through which they mediate signal
transduction.
• The type-III subset of the IFN family includes
three members: IFN-λ1, -λ2and-λ3 ,also
known as IL-29,IL-28A and IL-28B, respectively.
• Here,when referring to type-III IFNs, we use
the gene symbols IL29, IL28A and IL28B,but
the IFN- λ designations when referring to the
corresponding proteins to emphasize their
antiviral functions.
Organization and transcriptional
regulation of the IFN-λ
genes
• The IFN-λ proteins share common structural
features with the IL-10-related cytokines,
particularly IL-22; however, unlike IFN-λ, IL-22
does not induce antiviral activity in IL-22receptor-positive target cells.
• Phylogenetically, IL28A, IL28B and IL29 reside
somewhere between the type-I IFNand IL-10
gene families.
• As shown in Figure 1, IL28A, IL28B and IL29
are clustered together on chromosome 19 The
exon–intron structure of the IFN-λ genes is
similar to the organization of the genes
encoding the IL-10-related cytokines.
• the promoters for the IL28A and IL28B genes
are very similar, and share several
transcriptional regulatory elements in
common with the IL29 promoter,suggesting
that all three genes are co-regulated in a
similar manner.