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CASE CONFERENCE

Dr. Waqar Munir


Clinical Fellow Year 1
Infectious Disease

THE CASE
A 45 years old Egyptian gentleman known case of diabetes mellitus
and hypertension for 6 years.

He presented to the Gastroenterology Clinic 7 years ago when he


was found to be positive for Hepatitis C Antibody on routine blood
screening for blood donation.
He had no symptoms at that time, he denied any history of road
traffic accident, previous history of any surgical procedure or blood
transfusion.
He admitted to having dental manipulation done 2 years before
presentation.

On examination, unremarkable examination and no signs denoting


decompensated chronic liver disease.

His laboratory workup showed normal CBC, Urea and Electrolytes &
INR.
Mildly elevated transaminases however normal bilirubin and albumin.

Ultrasound liver showed fatty liver without any evidence of cirrhosis.

Hepatitis C Antibody: Positive


Hepatitis C Quantitative PCR: 169,000 copies/ml
Hepatitis C Genotype: 3
Liver Biopsy at that time showed Fibrosis grade F1.

He was started on treatment with Pegylated Interferon injections and


ribavirin for 48 weeks.

Viral load after 4 weeks dropped to 600 copies/ml.


However viral load again jumped to 300,000 copies/ml at the end of
48 weeks treatment.

No End Treatment Response (ETR) or Sustained Virological Response


(SVR) was achieved unfortunately.
The patient was followed up in Gastroenterology clinic as a treatment
non responder.

What is the percentage of HCV cure from pegylated interferon and


ribavirin?

For pegylated interferon and ribavirin treatment, response rate mostly


depends on the hepatitis C genotype.

Genotype 1 patients have around 45% chance of success with


pegylated interferon and ribavirin.
Genotype 2 or 3 patients have around 75% chance of success with
pegylated interferon and ribavirin.

He travelled to Egypt in 2013 and took a full course of treatment with


Sofosbuvir and Ribavarin for 24 weeks.

Viral load dropped to zero at ETR from 450,000 copies/ml.


However at 3 months followup he was found to have a viral load of
150,000 copies/ml.

No SVR achieved.

What is the percentage of SVR with Ribavirin & Sofosbuvir?

In the randomized, open-label BOSON trial, investigators enrolled


treatment-naive and treatment-experienced patients with genotype 2 or
3 chronic HCV infection, with or without cirrhosis, to receive one of three
treatment regimens: sofosbuvir plus ribavirin for 16 weeks, sofosbuvir plus
ribavirin for 24 weeks, and sofosbuvir plus ribavirin plus peginterferon
alfa-2a for 12 weeks.
Among the 592 patients enrolled in the study, 92% had genotype 3
infection.

For the treatment-naive patients with genotype 3 infection, the SVR 12


rates were 77% with the 16-week sofosbuvir plus ribavirin regimen, 88%
with 24 weeks of sofosbuvir plus ribavirin, and 95% with 12 weeks of
sofosbuvir plus ribavirin plus peginterferon.
For the treatment-naive patients with genotype 3 infection, the superiority
of the results with the 12-week regimen of sofosbuvir plus ribavirin plus
peginterferon was maintained in patients with or without cirrhosis.

He presented to Gastroenterology clinic after hearing about new


treatment options for HCV.

Is there another treatment option available for him?

INTRODUCTION
Chronic hepatitis C virus (HCV) infection is one of the most common
chronic liver disease and accounts for 8000 to 13,000 deaths each
year.
The majority of liver transplants performed in the United States are
for chronic HCV.
Globally, it was estimated that in 2005, more than 185 million people
had hepatitis C virus (HCV) antibodies (prevalence of 2.8 percent).
The existence of hepatitis C originally identifiable only as a type of
non-A non-B hepatitis was suggested in the 1970s and proven in
1989.

STRUCTURE
Hepatitis C virus (HCV) is a small (5565 nm in size),
enveloped, positive-sense single-stranded RNA virus of the
family Flaviviridae.
The hepatitis C virus particle consists of a core of RNA, surrounded by
an icosahedral protective shell of protein, and further encased in a
lipid envelope of cellular origin.

Structural proteins made by the hepatitis C virus include Core


protein, E1 and E2 embedded in the lipid glycoprotein envelope;
nonstructural proteins include NS2, NS3, NS4A, NS4B, NS5A,
and NS5B.

INTRODUCTION

INTRODUCTION

REPLICATION
The virus replicates mainly in the hepatocytes, where it is estimated
that daily each infected cell produces approximately fifty virions
(virus particles) with a calculated total of one trillion virions
generated.
HCV has a wide variety of genotypes and mutates rapidly due to a
high error rate on the part of the virus' RNA-dependent RNA
polymerase.
The mutation rate produces so many variants of the virus it is
considered a quasispecies rather than a conventional virus species.

Entry into host cells occur through complex interactions between virions
and cell-surface molecules.

Once inside the hepatocyte, HCV takes over portions of the


intracellular machinery to replicate.
The HCV genome is translated to produce a single protein of around
3011 amino acids. The polyprotein is then proteolytically processed
by viral and cellular proteases to produce three structural (virionassociated) and seven nonstructural (NS) proteins.

The NS proteins then recruit the viral genome into an RNA replication
complex, which is associated with rearranged cytoplasmic membranes.

RNA replication takes places via the viral RNA-dependent RNA


polymerase NS5B, which produces a negative strand RNA
intermediate.
The negative strand RNA then serves as a template for the production
of new positive strand viral genomes.
Nascent genomes can then be translated, further replicated or
packaged within new virus particles. New virus particles are thought
to bud into the secretory pathway and are released at the cell
surface.

INTRODUCTION

GENOTYPE & PREVALENCE


Based on genetic differences between HCV isolates, the hepatitis C
virus species is classified into seven genotypes (17) with several
subtypes within each genotype (represented by lower-cased letters).
Subtypes are further broken down into quasispecies based on their
genetic diversity.
Genotypes differ by 3035% of the nucleotide sites over the
complete genome.
The difference in genomic composition of subtypes of a genotype is
usually 2025%.

Subtypes 1a and 1b are found worldwide and cause 60% of all


cases.

TRANSMISSION
Most patients infected with HCV in the United States and Europe
acquired the disease through intravenous drug use or blood
transfusion, the latter of which has become rare since routine testing of
the blood supply for HCV was begun in 1990.

NATURAL HISTORY
Acute infection
Hepatitis C infection causes acute symptoms in 15% of cases which
are mild and vague, including a decreased appetite,
fatigue, nausea, muscle or joint pains, and weight loss.
Chronic infection

About 80% of those exposed to the virus develop a chronic infection


which is defined as the presence of detectable viral replication for at
least six months.

Most patients experience minimal or no symptoms during the initial


few decades of the infection.

Chronic hepatitis C can be associated with fatigue and mild cognitive


problems and later with signs and symptoms of decompensated liver
failure.
About 1030% of those infected develop cirrhosis over 30 years.
Those who develop cirrhosis have a 20-fold greater risk
of hepatocellular carcinoma which occurs at a rate of 2-6% per year.

DIAGNOSIS
There are a number of diagnostic tests for hepatitis C, including
HCV antibody enzyme immunoassay or ELISA, and quantitative
HCV RNA polymerase chain reaction (PCR).
HCV RNA can be detected by PCR typically one to two weeks after
infection, while antibodies can take substantially longer to form and
thus be detected.

TREATMENT
A greater understanding of the hepatitis C virus (HCV) genome and
proteins has enabled efforts to improve efficacy and tolerability of
HCV treatment.
Notably, this has led to the development of multiple direct-acting
antivirals (DAAs), which are medications targeted at specific steps
within the HCV life cycle.
DAAs are molecules that target specific nonstructural proteins of the
virus and results in disruption of viral replication and infection.
There are four classes of DAAs, which are defined by their mechanism
of action and therapeutic target. The four classes are nonstructural
proteins 3/4A (NS3/4A) protease inhibitors (PIs), NS5B nucleoside
polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase
inhibitors (NNPIs), and NS5A inhibitors

NS5A inhibitors

NS5B nucleotide
polymerase
inhibitors (NPI)

NS5B nonnucleoside
polymerase
inhibitors (NNPIs)

NS3/4A protease
inhibitors

Daclatasavir (DCV)

Sofosbuvir (SOF)

Dasabuvir (DSV)

Simepravir (SMV)

Elbasvir (EBR)

Paritapravir (PTV)

Ledipasvir (LDV)

Grazoprevir (GZR)

Ombitasvir (OBV)

Boceprevir (BOC)

Velpatasvir (VEL)

Telaprevir (TVR)

INDICATIONS FOR TREATMENT OF CHRONIC


HEPATITIS C: WHO SHOULD BE TREATED AND
WHEN?

Regimen

HCV Genotype
1a

1b

5 or 6

SOF + PR

12 wks

12 wks

12 wks

SMV + PR

12 wks (naive or relapse)


24 wks (partial/null)

12 wks (naive or relapse)


24 wks (partial/null)

Not
recommended

LDV/SOF

8-12 wks, no RBV

12 wks, no RBV

12 wks, no RBV

Not recommended

Not
recommended

Not recommended

12 wks + RBV

Not
recommended

SOF + SMV

12 wks, no RBV

12 wks, no RBV

Not
recommended

SOF + DCV

12 wks, no RBV

12 wks, no RBV

12 wks, no RBV

OBV/PTV/RTV
+ DSV
OBV/PTV/RTV

12 wks
+ RBV

12 wks,
no RBV

Regimen

HCV Genotype

1a

1b

5 or 6

SOF + PR

12 wks

12 wks

12 wks

SMV + PR

12 wks (naive or relapse)


24 wks (partial/null)

12 wks (naive or relapse)


24 wks (partial/null)

Not recommended

LDV/SOF

12 wks + RBV or 24 wks,


no RBV or 24 wks + RBV
if negative predictors

12 wks + RBV or 24 wks,


no RBV or 24 wks + RBV if
negative predictors

12 wks + RBV or 24 wks,


no RBV or 24 wks + RBV if
negative predictors

Not recommended

Not recommended

Not recommended

24 wks + RBV

Not recommended

SOF + SMV

12 wks + RBV or 24 wks,


no RBV

12 wks + RBV or 24 wks,


no RBV

Not recommended

SOF + DCV

12 wks + RBV or 24 wks,


no RBV

12 wks + RBV or 24 wks,


no RBV

12 wks + RBV or 24 wks,


no RBV

OBV/PTV/RTV
+ DSV
OBV/PTV/RTV

24 wks
+ RBV

12 wks
+ RBV

No Cirrhosis
Regimen

Compensated Cirrhosis
(Child-Pugh A)

GT2

GT3

GT2

GT3

SOF + PR

12 wks

12 wks

12 wks

12 wks

SOF + RBV

12 wks

24 wks

16-20 wks

Not
recommended

SOF + DCV

12 wks,
no RBV

12 wks,
no RBV

12 wks,
no RBV

24 wks
+ RBV

BACK TO OUR PATIENT


The gentleman is a SOF based therapy non responder.
Current recommendation based on genotype states:

Our patient was eligible for re treatment with Sofosbuvir &


Daclatasavir for 12 weeks duration without ribavirin as he had no
cirrhosis.
The patients viral load dropped to zero and he had a sustained
virological response (SVR).
He was discharged from Hepatitis Clinic afterwards in stable
condition.

REFERENCES
Uptodate
Medscape
EASL/AASL guidelines

THANK YOU