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 (55–65 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 (virion-associated) 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 (1–7) 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 30–35% of the nucleotide sites over the complete genome.

The difference in genomic composition of subtypes of a genotype is usually 20–25%.

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 10–30% 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 non-

nucleoside

polymerase

inhibitors (NNPIs)

NS3/4A protease

inhibitors

Daclatasavir (DCV)

Elbasvir (EBR)

Ledipasvir (LDV)

Ombitasvir (OBV)

Velpatasvir (VEL)

Sofosbuvir (SOF)

Dasabuvir (DSV)

Simepravir (SMV)

Paritapravir (PTV)

Grazoprevir (GZR)

Boceprevir (BOC)

Telaprevir (TVR)

INDICATIONS FOR TREATMENT OF CHRONIC HEPATITIS C: WHO SHOULD BE TREATED AND WHEN?

Regimen HCV Genotype

1a 1b 4 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

OBV/PTV/RTV + DSV

12 wks + RBV

12 wks, no RBV

Not recommended Not recommended

OBV/PTV/RTV 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

Regimen HCV Genotype

1a 1b 4 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

OBV/PTV/RTV

+ DSV

24 wks

+ RBV

12 wks

+ RBV

Not recommended Not recommended

OBV/PTV/RTV 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

Regimen

No Cirrhosis 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 patient’s 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