Chronic Hepatitis C

CURE
is Here
is Simple
is Complete

Angela D. Salvaña, MD
 Hepatitis
CASE C Virus

• Single-stranded RNA virus

• Percutaneous, nonpercutaneous, or
sporadic transmission
• Cause of disease cannot be
established in a third of patients

https://medlineplus.gov/hepatitisc.html
Sleisinger and Fordtran's Gastrointestinal and Liver Diseases 10th Edition
 Global
CASE Prevalence of HCV
Approximately 160-185 million people around the world have been infected with the
hepatitis C virus (HCV), of whom 350,000-500,000 die each year

EU – 5.5 to 6.5 Million

United States – 3.2 Million

Egypt – 6 Million

South-East Asia – 30 Million

Africa – 28 Million
1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17:107-115. 2. Holtzman D. Infectious Diseases Related to Travel. Centers for Disease Control and Prevention. Published August 2013.
http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectiousdiseases-related-to-travel/hepatitis-c. Accessed July 2014. 3. Chak E, Talal AH, Sherman KE, Schi ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090-
1101. 4. Arab Republic of Egypt, Ministry of Health and Population, National Committee for the Control of Viral Hepatitis. Egyptian National Control Strategy For Viral Hepatitis 2008-2012; April 2008. https://www.pasteur.fr/ip/resource/filecenter/document/01s-00002i-
03t/nsp-10-april-2008-final.pdf. Accessed July 2014. 5. Mohamoud YA, Murntaz GR, Riome S, Miller D, Abu-Raddad LJ.The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infectious Diseases. 2013;13:288-308.
http://biomedcentral.com/1471-2334/13/288. Accessed March 2014. 6. World Health Organization. Regional strategy for the prevention and control of viral hepatitis. Published 2013. http://www.searo.who.int/entity/emerging_diseases/topics/CD_282.pdf?ua=1. Accessed

3
September 2013. 7. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1&ua=1. Published April 2014. Accessed July 2014. 8.
WHO Fact Sheet. Hepatitis C [Internet]. 2014 [updated April 2014; cited 2015 Mar 26]. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/ 9. Radha K. Dhiman. Future of therapy for Hepatitis C in India: A Matter of Accessibility and Aordability? Journal of
Clinical and Experimental Hepatology. 2014; 4(2): 85–86 10. Center for Disease Analysis. Hepatitis C World Map. Availablefrom: http://www.centerforda.com/HepC2013b/HepMap.html

This document contains confidential and proprietary information of Mylan N.V. Unauthorized use, duplications, dissemination or disclosure to third parties is strictly prohibited
 Philippine Prevalence Data

• Arguillas et al 1991- 2.2% of 392 blood donors,

1.6% of 123 medical and paramedical personnel in
Davao

• Katayama et al 1996 – 2.3% of 800 blood donors

(+)anti-HCV, 78% (+)RNA; 4.6% of 502 inmates
(+)anti-HCV, 83% (+)RNA in Metro Manila

• Subida et al 1997 – 0% of 50 women in Metro

Manila
 Philippine Prevalence Data
• Agdamag et al 2005 - 70.1% of 87 IV drug users,
16.3% of 43 inhalational drug users, 0% of 130 sex
workers in a cohort in Cebu

• Rodenas et al 2006 – 0.12% of 6,560 blood donors

at East Avenue

• WHO bulletin 2007 - 0.3% of 63,166 hospital-based

blood donors, 0.001% of 11,014 potential OFWs
 Risk Factors for HCV Infection

• blood transfusion before 1992

• current or past injection drug use

• multiple sexual partners, unprotected sex, sex with

HCV-infected person or injection drug user

• long-term hemodialysis

http://www.hcvguidelines.org/may24,2018.

Screening for Hepatitis C Virus Infection in Adults: U.S. Preventive Services Task Force
Recommendation Statement. Ann Internal Med vol 159, no 5. Sept 2013.
 Risk Factors for HCV Infection

• incarceration

• unregulated tattoos

• other percutaneous exposures

• perinatal exposure 5.1-6.7% risk

http://www.hcvguidelines.org/may24,2018.
Screening for Hepatitis C Virus Infection in Adults: U.S. Preventive Services Task Force
Recommendation Statement. Ann Internal Med vol 159, no 5. Sept 2013.
Percutaneous Exposure in Healthcare
Workers
• 0.1% (0.3-4% longitudinally) risk among healthcare
workers

• type of needle i.e. hollow vs solid, infusion vs

withdrawal

• volume of inoculum, viral load, HIV status

• rare transmission via mucous membrane exposure

• no documented transmission in skin exposure to blood

without needle puncture

• environmental contamination not significant www. cdc.gov/mmwr/preview/mmwrhtml/rr5011a.htm

Sleisinger and Fordtran's Gastrointestinal and Liver Diseases 10th Edition
 Healthcare-Associated HCV
Transmission
• Most outpatient cases are seen in hemodialysis
units.

• Majority of cases involve breaches in protocol of

healthcare units or drug diversion.

https://www.cdc.gov/hepatitis/outbreaks/pdfs/HealthcareInvestigationTable.pdf
Hepatitis
CASE C Virus (Phases)

<6 months

Spontaneous
HCV Resolution
Infection

Potential for
≥6 months Progression to
Advanced
Chronic Liver Disease
HCV

Acute HCV
• Detectable HCV RNA <6 months
• Frequently symptom-free
• May spontaneously resolve
Chronic HCV
• Detectable HCV RNA ≥6 months
• More common
• Potential for progression to advanced liver disease
 Natural History
• Chronic hepatitis develops in 50-90% of persons with
acute HCV infection.

• Most remain asymptomatic.

• An early, multispecific T cell response occurs in

those who clear the virus.

• Individual course, progression, or non-progression of

liver disease is highly variable.

Sleisinger and Fordtran's Gastrointestinal and Liver Diseases 10th Edition

http://www.hcvguidelines.org/may24,2018.
 Natural History

• Cirrhosis develops in 16% of patients within 20 years

after onset.

• Cirrhosis will develop in most patients by age 65

regardless of age of infection.

• Normal ALT levels do not exclude fibrosis progression.

• Viral load is not related to degree of liver damage or

fibrosis.

Sleisinger and Fordtran's Gastrointestinal and Liver Diseases 10th Edition

 Natural History
• HCC due to HCV usually does not develop in
noncirrhotic livers.

• Five-year risk of developing HCC is 7-30% in

cirrhotic patients.

Sleisinger and Fordtran's Gastrointestinal and Liver Diseases 10th Edition

 Cirrhosis:
Compensated
CASE vs. Decompensated
Compensated cirrhosis: Decompensated cirrhosis:
• Heavily scarred • Extensively scarred
• Able to carry out many important • Unable to perform liver function
liver synthetic functions adequately
• Few-to-no symptoms

Symptoms of
Decompensated Cirrhosis
• Encephalopathy
• Variceal bleeding
• Jaundice
• Ascites Ascites

Once cirrhosis develops, it may progress at any time to a decompensated state.

Averhoff FM, et al. Clin Infect Dis 2012;55(Suppl 1):S10–5;

Perz JF, et al. J Hepatol 2006;45:529–38
 Liver
CASE Function Tests
Possible Causes of Elevated
ALT Levels
• Liver necrosis
• Viral infections
• Hemochromatosis
• Liver ischemia
• Liver tumor
• Hepatotoxic medications
• Pancreatitis
• Some patients are only diagnosed due to elevated liver enzymes on routine blood
work.
• About 1/3 of HCV patients have normal liver enzymes.
Possible Causes of Elevated
AST Levels
• Acute kidney failure
• Heart attack
• Hemochromatosis
• Hemolytic anemia
• Viral infections
• Liver ischemia
• Liver tumor
• Hepatotoxic medications
• Muscle disease or trauma
• Pancreatitis
• Others: deep burns, heart
procedures, seizure,
surgery
 Genotyping
CASE
Knowing the genotype is helpful in:

• Defining the epidemiology of hepatitis C

• Predicting the likelihood of a treatment response
• Determining the optimal regimen of treatment and
duration of therapy

Depending on the nomenclature system, as many as 11 different

genotypes of HCV have been detected; 6 are most common.

To be defined as a separate genotype, the genetic information in the

viruses must diverge ≥30%.

Some genotypes are further subdivided into subtypes, which typically

have 20% to 25% divergence.
 Global Distribution of HCV
CASE
by Genotype
Genotype 1 is the most common worldwide and
represents about 75% of HCV cases in the United States

KEY

Genotype 1
Genotype 2
Genotype 3
Genotype 4
Genotype 5
Genotype 6

Figure source:
http://www.who.int/vaccine_research/documents/ViralCancer7.pdf
 Transient
CASE Elastography (Fibroscan)

• A mechanical pulse (50 Hz) is generated at the skin surface, which is

propagated through the liver. The velocity of the wave (meters per
second) is measured by ultrasound

• The velocity is directly correlated to

the stiffness of the liver (measured in
kilopascal).
• The stiffer the liver, the greater the
degree of fibrosis.
Liver
CASE Biopsy
Reasons for Performing a Liver Biopsy
• Staging degree of liver injury
• Differentiating etiologies of liver disease

Limitations of a Liver Biopsy

• Invasiveness
• Sampling error
• Potential for complications
Whom
CASE to Treat

Treat all patients except those with a short life

expectancy that cannot be remediated by HCV
therapy or liver transplant or other directed
therapy.

http://www.hcvguidelines.org/may24,2018.
Goals
CASE of Treatment

• Reduce all-cause mortality

• Reduce end-stage liver disease and hepatocellular
carcinoma
• Achieve virologic cure

http://www.hcvguidelines.org/may24,2018.
Sustained Virological Response (SVR)
CASE

• SVR is the continued absence of detectable HCV RNA

for at least 12 weeks after completion of therapy.
• SVR is a marker for cure of HCV infection.

http://www.hcvguidelines.org/may24,2018.
 Importance
CASE of Achieving SVR
Liver-related mortality or
liver transplantation (%)

Liver-related mortality or liver transplantation

P<0.001
n=530
Without SVR

With SVR

Time (y)

Hepatocellular carcinoma (HCC)

P<0.001
Hepatocellular
carcinoma (%)

n=530

Without SVR

With SVR

Time (y)
van der Meer AJ, et al. JAMA 2012;308:2584–93
History
CASE of HCV Treatment
Evolution of SVR rates in patients with HCV

Peg Interferon and Ribavirin Era Start of interferon and

ribavirin free treatment
Adapted from 1. Strader DB, et al. Hepatology 2004;39:1147–71; 2. Vertex Pharmaceuticals. Incivek (telaprevir) Prescribing Information, 2013; 3. Merck & Co. Victrelis (boceprevir) Prescribing
Information, 2014; 4. Manns M, et al. EASL 2013; Oral #1413;
5. Lawitz E, et al. APASL 2013; Oral #LB-02; 6. Lawitz E, et al. N Engl J Med 2013;368:1878–87
Treatment-Naïve Chronic Hepatitis C

2018 Update to the Consensus Statements on the Diagnosis and Treatment of Hepatitis C
Hepatology Society of the Philippines
Treatment-
Naïve
Chronic
Hepatitis C

2018 Update to the

Consensus Statements
on the Diagnosis and
Treatment of Hepatitis C
Hepatology Society of the
Philippines
Treatment-Experienced Chronic Hepatitis C

2018 Update to the Consensus Statements on the Diagnosis and Treatment of Hepatitis C
Hepatology Society of the Philippines
 Treatment-Experienced
Chronic Hepatitis C

2018 Update to the Consensus Statements

on the Diagnosis and Treatment of Hepatitis C
Hepatology Society of the Philippines
ION-1
ION-3
ION-2
2018 Update to the Consensus Statements on the Diagnosis and Treatment of Hepatitis C
Hepatology Society of the Philippines
Dosing
• Sofosbuvir (SOF) 400mg
• Ledipasvir (LED) 90mg
• Daclatasvir (DCV) 60mg, increased to 90mg with
some ARVs
• Velpatasvir (VEL) 100mg
• Ribavirin (RBV) start at 600mg and increase to
1,000 mg if <75kg, 1,200 mg if ≥ 75kg as tolerated
• Extension to 24 weeks for decompensated cirrhosis
if HCV RNA is detectable at 12 weeks
2018 Update to the
Consensus Statements
on the Diagnosis and
Treatment of Hepatitis C
Hepatology Society of the
Philippines
Sofosbuvir
CASE and Ledipasvir
Mechanism of Action

Daclatasvir
Treatment of Patients with
HIV/HCV Co-infection
 How many people are co-infected
with
CASEHIV/HCV?
Worldwide

40 million

HIV HCV

10 million
175 million

1. NACO Annual Report 2013–2014. Available at:

http://www.naco.gov.in/upload/2014%20mslns/NACO_English%202013-14.pdf [accessed April 2015];
2. Sawant S, et al. Indian J Sex Transm Dis AIDS 2010;31:126; 3. Tripathi AK, et al. J Assoc Physicians India
2007;55:429–31; 4. Sarvanan S, et al. World J Gastroenterol 2007;13:5015–20; 5. Ponamgi SPD, et al. Indian J
Med Microbiol 2009;27:12–6; 6. Chandra N, et al. Indian J Med Res 2013;138:950–4
Features of HCV Infection in PLHIV
• Co-infected patients have higher rates of liver-related
morbidity and mortality than HCV-monoinfected patients.
• Co-infected patients have higher rates of progression to
fibrosis and cirrhosis.
• Efficacy and adverse events with direct-acting antivirals
(DAAs) are similar between HCV-monoinfected and co-
infected patients.
• Co-infected patients should be treated just like HCV-
monoinfected patients, taking into account DAA interactions
with ARVs.
• Goal of treatment is cure of HCV infection.
• Ongoing care of chronic liver disease is unchanged.

https://www.hcvguidelines.org/unique-populations/hiv-hcv
DRUG INTERACTIONS BETWEEN DAAs AND ARVs,
PREFERRED REGIMENS

https://www.hcvguidelines.org/unique-populations/hiv-hcv
DRUG INTERACTIONS BETWEEN DAAs AND ARVs,
ALTERNATIVE REGIMENS

https://www.hcvguidelines.org/unique-populations/hiv-hcv
 ON DAAs AND ARVs

• LDV/SOF should not be administered as a

shortened regimen of 8 weeks.
• Ribavirin is contraindicated for use with zidovudine
due to worse anemia.
• Given the limited selection of ARVs locally, consider
LED/SOF for genotypes 1, 4, 5 and 6 and DCV/SOF
for genotypes 2 and 3.
• Consider using VEL/SOF for any genotype only if
lopinavir/ritonavir is used in place of efavirenz.

https://www.hcvguidelines.org/unique-populations/hiv-hcv
2018 Update to the Consensus Statements on the Diagnosis and Treatment of Hepatitis C
Hepatology Society of the Philippines
Conclusions
• Screen patients with risk factors.
• Treat all patients with reasonable life expectancies.
• The goal is cure.
• Tailor treatment regimens according to treatment
status, the presence or absence of cirrhosis, liver
function, and presence of co-infection.
• Special populations require co-management with a
gastroenterologist or hepatologist.
 Mylan
CASE DAAs to cover all Genotypes

 Manufactured under an agreement and technology transfer from Gilead

 Manufactured in a state-of-the art USFDA approved plant
 Proven bioequivalence with SOVALDI and HARVONI
 The only Daclatasvir available in Philippines

CURE
is Here
is Simple
is Complete
Thank You