Chronic Hepatitis C

Estimated Global HCV Prevalence

170 million people
 It is estimated by the WHO
that ~170 million individuals,
or 3.1% of the world
population, are infected with
HCV—
 >5 X the number of PLWHA.
 There is an estimated 3–4
million new infections
occurring each year.
 Global Burden of HCV Disease
 There is considerable
geographic variation in the
prevalence of HCV infection.
 In the Americas,
approximately 1.7% of the
population is currently living
with HCV and genotypes 1
Europe
(~75%), 2 and 3 dominate . 8.9 million Western
Pacific
 In Egypt, there are some (1.03%)
62.2 million
areas in which one out of (3.9%)
every 5 individuals has chronic The Southeast Asia
hepatitis C. Americas 32.3 million
13.1 million Eastern (2.15%)
 The virus spread in Egypt (1.7%) Africa Mediterranen
31.9 million 21.3 million
drastically as a result of unsafe (5.3%) (4.6%)
injection practices during a
campaign to eradicate
schistosomiasis.
 Natural History HCV
• Mode of infection
• Risk factors for disease progression
– Age,
– Alcohol,
– Co-infections
• Generally, asymptomatic acute phase
• Majority of acute infections become chronic
• Long term duration of cirrhosis before HCC
 Chronic Hepatitis C
 Progression of liver disease in patients with chronic hepatitis C
has been reported to be more likely in patients with
1. older age,
2. longer duration of infection,
3. advanced histologic stage and grade,
4. genotype 1,
5. more complex quasispecies diversity,
6. increased hepatic iron,
7. concomitant other liver disorders
8. HIV infection, and
9. obesity.
 Chronic Hepatitis C

No other epidemiologic or clinical features of chronic

hepatitis C are predictive of eventual outcome, e.g.,

1. severity of acute hepatitis,

2. level of aminotransferase activity,
3. level of HCV RNA,
4. presence or absence of jaundice during acute hepatitis.
HCV Natural History

Acute Hepatitis C

6 months – 1 year Faster progression:

• Older Age at Infection
20-50 Years

Chronic Hepatitis • Alcohol

75-85 % • HIV infection
• Post-Transplant

Cirrhosis 20 %

Source: Di Bisceglie, Hepatology 2000

Natural History of Chronic HCV
Infection
Fibrosis Cirrhosis Hepatocellular Carcinoma
(with cirrhosis)

Decompensated cirrhosis:

1. Ascites
2. Bleeding varices
3. Hepatic encephalopathy
4. Jaundice
HCV Lifecycle Overview
Steps in the HCV life cycle:
1. HCV virus infects human - circulates in the blood as a lipoviral
particle.
2. It enters the hepatocytes by binding its envelope proteins (E1, E2)
to CD81, SR-B1, claudin and occludin co-receptors.
3. Cytoplasmic release and uncoating of RNA genome
4. IRES-mediated (internal ribosomal entry site) translation and
polyprotein processing by cellular and viral proteases ( into 10 viral
proteins)
5. RNA replication (creation of minus strand template followed by
production of plus strand RNA copies) occurs at an endoplasmic
reticulum membrane−derived replication complex (the
membranous web), which includes the lipid droplet (LD) and
nonstructural viral proteins NS4A−NS5B.
6. Packaging and assembly by the Golgi apparatus and subsequently
released by the cell.
7. Virion maturation
8. Release from host cell
Lifecycle: Viral Polyprotein

The viral
RNA
undergoes
translation
resulting in
a single
viral
polyprotein
.
 Viral Enzymes
• NS3/4A protease assists in the downstream cleavage of
viral peptides. It also has ability to cleave and inactivate
host proteins that aid in antiviral activity (IRF-3)
• NS5B RNA-dependent RNA polymerase (RdRp) facilitate
viral replication by copying a positive strand RNA into
negative strand intermediate ( a template for more viral
RNA genomes)
• NS5B RdRp lacks proof reading capabilities and therefore
mutations of HCV genome occurs at a rate of 10-4 per
nucleotide
• NS5A “replicase” assists in viral replication and viral
assembly.
HCV Clinical Management
HCV Screening Is the First Step
on the Road to a Cure for HCV
Infection
Cure
Assessment

Testing Treatment

Counseling
Screening
 Who to Screen?

3 approaches
Population Risk-factor based
Birth cohort
screening, including screening e.g., PWID,
screening
antenatal MSM, prisoners

• No current universal screening program

• Risk based screening: population dependent
• Birth cohort - in USA and Japan
 Risk Factors: Who to Screen?
• IDU
• Nasal cocaine
• Transfusions
• Needle stick injury
Parenteral • Tattoos
• Body piercing
• Manicures
• Household items
• Hemodialysis
• Multiple partners
• Traumatic
• HIV (+)
Sexual • Use of a CSW
• Rectal contact
• MSM
• High viral load
Perinatal • HIV (+)
Hepatitis C Virus: Diagnostic Testing

DIAGNOSTIC TEST TYPE

Specifications Serologic Virologic
Mode of detection Antibodies Virus

Sensitivity > 95% > 98%

Specificity Variable > 98%

Detection postexposure 2-6 months 2-6 weeks

Use Screening Confirmation

 HCV Antibody Testing
ELISA screening tests
• Detect circulating HCV
antibodies
• Sensitivity: 97% to 100%
False Positives More Likely in:
Previous cleared infection
Autoimmune disease
HIV positive
• Positive predictive value
– 95% with risk factors and
elevated ALT
– 50% without risk factors and
normal ALT
False Negatives More Likely in:
Severely immunosuppressed
patients
Transplantation recipients
Patients with chronic renal failure
on dialysis
HIV positive
 HCV Confirmation Test
Detection of HCV RNA
o All persons with positive anti-HCV antibody test must undergo HCV
PCR testing for the presence of the HCV itself to determine

• whether current infection is present and

• whether there is an indication for treatment
o HCV PCR is the most common method to detect viral RNA
o It is also used to quantify the virus for treatment monitoring purpose
o HCV PCR is not widely accessible and costs ≥100 USD per test
• A great need exists for an affordable:

– Point Of Care HCV Viral load or HCV Ag test (with good

sensitivity)
– Flexible PCR platforms (Multi-test: HBV-HIV-HCV)
 Determination of HCV Genotype

PCR
1a
1b
2a
• HCV genotype – currently:
– Determines choice of regimen
– Predictor of response
– Influence duration of therapy 2b
3a
• All patients should have genotype determined 3b
prior to initiating therapy 4 e.g., InnoLipa
5
• Pan-genotypic treatment potentially
eliminates need for genotyping
Fibrosis Assessment = Disease
Severity

Liver Serum FibroScan

Biopsy Biomark
ers
Aim of HCV Treatment = Cure
Goal of HCV treatment is viral cure
HCV life Cycle favors resistance development not persistence
HIV HBV HCV

(+) (-) (+)

NS5B
RT

NS5B
RT
Human
RNApol RT

HIV HBV HCV

Stable genome Provirus cccDNA (none)
Virion NA polymerase Host RNApol HBV RT HCV NS5B
Error-prone replications per cell One Multiple Multiple
Plasticity of genome High Constrained Very high
Recombination Common Common Rare 2
 SVR (Cure) and Improved Outcomes
• SVR
– Durable
– Improved quality of life
– Leads to improved histology
– Leads to clinical benefits
• Reduced risk of death
• Decreases decompensation
• Prevents de novo esophageal varices
• Decreases risk of hepatocellular carcinoma
 HCV Lifecycle – DAA Targets
NS5A inhibitors

Block replication complex formation and

assembly
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
Translation
and ER lumen
(+) RNA LD
Virion
polyprotein LD assembly
processing
NS5B polymerase
LD inhibitors
NS3/4 Membranous
protease web Nucleoside/nucleoti
inhibitors ER lumen de
RNA Nonnucleoside
replication
 HCV Lifecycle – The DAAs

...asvir

Daclatasvir
Ledipasvir
Ombitasvir
NEW
Elbasvir
Pibrentasvir
...previr velpatasvir

Simeprevir ...buvir
NEW
Grazoprevir Paritaprevir/r
Sofosbuvir
glecaprevir Asunaprevir
Telaprevir Dasabuvir
Boceprevir
Oral DAA Regimens – Guiding Principles

 Combine drugs from different

classes
o Protease (NS3/4A) inhibitors
o Polymerase (NS5B) inhibitors
o NS5A inhibitors

 Multiple drugs combined to produce

greater efficacy and reduce risk of viral
resistance (not unlike HIV ART)
 Indications for HCV Treatment
Treatment prioritization needs to be applied in resource-
limited settings
Treatment priority Patient group
. Patients with significant fibrosis (F3) or cirrhosis (F4),
including decompensated cirrhosis
. Patients with HIV coinfection
. Patients with HBV coinfection
. Patients with an indication for liver transplantation
Treatment should be prioritized
. Patients with HCV recurrence after liver transplantation
. Patients with clinically significant extra-hepatic
manifestations
. Patients with debilitating fatigue
. Individuals at risk of transmitting HCV
Treatment is justified . Patients with moderate fibrosis (F2)
. Patients with no or mild disease (F0-F1) and none of the
Treatment can be deferred
above-mentioned extra-hepatic manifestations
. Patients with limited life expectancy due to non-liver
Treatment is not recommended related
comorbidities
 Treatment with Intent to
Prevent Transmission to Others

 Active injection drug users

 Incarcerated people
 Men who have sex with men with
high-risk sexual practices
 Patients on long-term haemodialysis
 HCV-infected women of childbearing
age who wish to be pregnant
 Adverse Effects of DAAs

Ribavirin
3D Sofosbuvir SOF/LDV
• Hemolytic
• Rash • Fatigue • Fatigue
• Pruritis • Nausea
anaemia
• Photosensitivity • Headache • Rash
• Unconjugated • Insomnia
hyperbilirubinemia
• Fatigue • Asthenia
• Teratogenic
Important Data in Choosing a Regimen

• Genotype
• HCV treatment history
– Peg-Interferon and ribavirin regimen?
– Previous Protease Inhibitor?
• Fibrosis stage?
– Options for fibrosis assessment
– If cirrhosis, is it decompensated?
 Non-Cirrhotic
*Treatment-Naïve or Peg-IFN/Ribavirin-Experienced Genotype
1, 4, 5

HCV Genotype
Regimen
1a 1b 4 5
LDV/SOF 8-12 wks,† no RBV 12 wks, no RBV 12 wks, no RBV

OBV/PTV/RTV + 12 wks 12 wks, Not recommended Not recommended

DSV + RBV no RBV

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

DCV, daclatasvir; DSV, dasabuvir; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV,
ritonavir; SMV, simeprevir; SOF, sofosbuvir;
*Recommendations the same for HCV-monoinfected and HCV/HIV-coinfected patients.
†8 wks may be used in treatment-naïve patients without cirrhosis if baseline HCV RNA <6 million IU/mL, but

should be done with caution, especially in patients with F3 fibrosis.

ropean Association for the Study of Liver Disease Hepatitis C Treatment
Guidelines. April 2015.
 Compensated Cirrhosis
*Treatment-Naive or Peg-IFN/Ribavirin-Experienced Genotype 1, 4, 5

HCV Genotype
Regimen
1a 1b 4 5 or 6
LDV/SOF 12 wks + RBV or 24 wks, 12 wks + RBV or 24 wks, 12 wks + RBV or 24 wks,
no RBV or 24 wks + RBV if no RBV or 24 wks + RBV if no RBV or 24 wks + RBV if
negative predictors negative predictors negative predictors

OBV/PTV/RTV 24 wks 12 wks Not recommended Not recommended

+ DSV + RBV + RBV

OBV/PTV/RTV Not recommended 24 wks + RBV Not recommended

SOF + SMV 12 wks + RBV or 24 wks, 12 wks + RBV or 24 wks, Not recommended
no RBV no RBV

SOF + DCV 12 wks + RBV or 24 wks, 12 wks + RBV or 24 wks, 12 wks + RBV or 24 wks,
no RBV no RBV no RBV

DCV, daclatasvir; DSV, dasabuvir; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV,
ritonavir; SMV, simeprevir; SOF, sofosbuvir;
*Recommendations the same for HCV-monoinfected and HCV/HIV-coinfected patients.
 Treatment-Naive Genotype 1a
Patients Without Cirrhosis

RECOMMENDED DURATION RATING

Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir 12 weeks I, A
(100 mg)
Daily fixed-dose combination of glecaprevir (300 8 weeks I, A
mg)/pibrentasvir (120 mg)
Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir 12 weeks I, A
(400 mg)
Daily fixed-dose combination of sofosbuvir (400 12 weeks I, A
mg)/velpatasvir (100 mg)
 HCV/HIV Coinfection
• No longer considered difficult to cure
• Same recommendations as in HCV mono-infected
patients
• Consider drug–drug interactions
– Avoid combination of LDV and tenofovir if CrCl < 60 mL/min or
if receiving tenofovir with RTV-boosted PIs
– When LDV/SOF and tenofovir are co-administered with ART -
monitor for nephrotoxicity
– Adjust/withhold RTV if receiving a boosted PI with
OMV/PTV/RTV + DSV
– Adjust DCV with atazanavir/RTV, efavirenz, or etravirine
• DCV + SOF ± RBV is recommended when ART regimen
changes cannot be made to accommodate other DAAs
 HCV in Pregnancy
 All pregnant women should be tested for HCV infection,
ideally at the initiation of prenatal care

 For women of reproductive age with known HCV

infection, antiviral therapy is recommended before
considering pregnancy, whenever practical and feasible,
to reduce the risk of HCV transmission to future offspring.

 Treatment during pregnancy is not recommended due to

the lack of safety and efficacy data.
 Cont….
 No specific risk factor predicts transmission and no
specific intervention (eg, antiviral, mode of delivery, or
others) has been demonstrated to reduce transmission

 Breastfeeding is not contraindicated in women with HCV

infection, except when the mother has cracked,
damaged, or bleeding nipples, or in the context of HIV
coinfection.

 Women with HCV infection should have their HCV RNA

reevaluated after delivery to assess for spontaneous
clearance.