1. Taking Steps to Improve the Management of Chronic HCV
This educational program and speaker are sponsored by
Gilead Sciences, Inc.

2. Goals and Objectives
Gain a better understanding of the epidemiology and natural history of CHC
Review HCV screening recommendations and the importance of assessing CHC patients prior to initiating antiviral therapy
Understand CHC treatment goals and patient monitoring while on treatment
Learn the potential benefits of achieving SVR
Review recommendations for post-treatment monitoring according to the results of treatment
Transition
This slide outlines the goals and objectives of this presentation on the management of chronic hepatitis C virus (HCV).
Key Points
This presentation is designed to provide an overview of the management of patients with chronic HCV infection. The goals and objectives are shown here:
To gain a better understanding of the epidemiology and natural history of chronic HCV (CHC)
Review HCV screening recommendations and the importance of assessing CHC patients prior to initiating antiviral therapy
Understand CHC treatment goals and patient monitoring while on treatment
Learn the potential benefits of achieving sustained virologic response (SVR)
Review recommendations for post-treatment monitoring according to the results of treatment
CHC=chronic hepatitis C virus; HCV=hepatitis C virus; SVR=sustained virologic response.

3. Program Outline Module 1: Overview of Chronic HCV Infection
HCV epidemiology
Natural history of HCV infection
Module 2: Pre-treatment Assessment
Recommended HCV screening guidelines
Patient assessment prior to starting antiviral therapy
Module 3: Managing HCV Therapy
HCV treatment goals
Patient monitoring on treatment
Module 4: Post-treatment Follow-up
The potential benefits of achieving SVR
Patient monitoring following antiviral therapy
Transition
This slide provides an outline of the 4 modules of the presentation.
Key Points
Module 1 provides and overview of chronic HCV infection, including a review of:
HCV epidemiology
Natural history of HCV infection
Module 2 looks at the recommended monitoring prior to starting antiviral treatment for chronic HCV
Recommended HCV screening guidelines
Patient assessment prior to starting antiviral therapy
Module 3 discusses key concepts related to the management of patients receiving HCV therapy
HCV treatment goals
Patient monitoring on treatment
Module 4 discusses post-treatment follow-up, including
The potential benefits of achieving SVR
Patient monitoring following antiviral therapy

4. Module 1: Overview of Chronic HCV Infection

5. At Least 3.5 Million People in the United States Have Chronic HCV
Approximately 3.5 million people in the United States are chronically infected with HCV (1.3%)1,a
Including populations excluded from NHANES (e.g., the incarcerated, homeless, institutionalized, and those living on Native American reservations) brings the total estimate to 4.6 million2
Seroprevalence is higher in1
birth cohort (3.5%)
Non-Hispanic blacks (2.2%)
Males (1.9%) vs females (1.1%)
Approximately 9% of all diagnosed individuals have been successfully treated3,b
About 9% of all diagnosed persons successfully treated
Transition
The estimated prevalence of chronic HCV infection in the United States is at least 3.5 million individuals.
Key Points
Using data from the National Health and Nutrition Examination Survey (NHANES), this slide shows the estimated prevalence of CHC in the United States to be approximately 3.5 million individuals (1.3%)1
However, because NHANES did not sample high-risk groups including the incarcerated, homeless, or institutionalized individuals, the actual prevalence is likely higher1
In a recent review, Edlin et al estimated that populations not accounted for in the NHANES data (including persons who are active military personnel, homeless, hospitalized, incarcerated, institutionalized, and those living on Native American reservations) contribute an additional 900,000 or more HCV-infected individuals, bringing the total estimate to at least 4.6 million2
HCV seroprevalence is higher in the following groups1:
birth cohort (3.5%)
Non-Hispanic blacks (2.2%)
Males (1.9%) vs females (1.1%)
When one looks at the treatment cascade for CHC, it is estimated that half of all of those infected with HCV remain undiagnosed
Approximately 9% of all persons diagnosed with CHC have been successfully treated3
References
Ditah I, et al. J Hepatol. 2014;60:
Edlin BR, et al. Hepatology. 2015;62:
Yehia BR, et al. PLoS ONE. 2014;9:1-7.
NHANES=National Health and Nutrition Examination Survey.
aNHANES data as of 2010.
bNHANES data,
Ditah I, et al. J Hepatol. 2014;60:
Yehia BR, et al. PLoS ONE. 2014;9:1-7.
Edlin BR, et al. Hepatology. 2015;62:

6. HCV Genotypes by Geographic Region
HCV genotypes in the
United States
GT 1 is most common, accounting for ~78% of HCV infections2a
GT 1a subtype is twice as common as GT 1b
Transition
On this map, we see the variations in the prevalence of individual HCV genotypes (GTs) in specific geographic regions around the globe.
Key Points
Globally, the prevalence of HCV GTs varies by geographic region, as indicated on the map shown here1
Looking at the United States, GT 1 is the most common and accounts for nearly 78% of HCV infections,2 with smaller proportions of other GTs
References
World Gastroenterology Organisation. Diagnosis, management and prevention of hepatitis C
Nainan OV, et al. Gastroenterology. 2006;131:
GT=genotype.
aDerived from HCV RNA–positive participants in NHANES III conducted 1988 to 1994 (N=275).
World Gastroenterology Organisation. Diagnosis, management and prevention of hepatitis C
Nainan OV, et al. Gastroenterology. 2006;131:

7. HCV Genotypes Present Substantial Genetic Variability
HCV types may vary by as much as 33% over the whole viral genome1
Genetic heterogeneity of HCV may account for differences in disease outcome and response to treatment1
HCV phylogenetic tree 3 5 6 2 4 1 a b c
Transition
Here we have a simplified schematic of the HCV phylogenetic tree.
Key Points
As shown on this simplified phylogenetic tree, there is substantial genetic heterogeneity among the common HCV genotypes
The degree of difference among the 6 GTs is represented by their relative distance from each other: the further they are apart on this schematic, the greater the genetic difference1
Comparison of published sequence of HCV has led to the identification of several distinct types that may differ from each by as much as 33% over the whole viral genome2
The differences among the genotypes may account for differences in disease outcome and response to treatment2
References
Poon AFY, et al. PLoS One. 2013;8:e78122.
Zein NN. Clin Microbiol Rev. 2000;13:
Adapted from Franciscus A. HCSP Fact sheet
Zein NN. Clin Microbiol Rev. 2000;13:

8. HCV Can Be Cured HCV Unlike HIV and HBV, HCV is curablea
viral RNA
Unlike HIV and HBV, HCV is curablea
HCV RNA remains in the cytoplasm and does not integrate into host DNA1
HCV is highly genetically variable due to its:
High replication rate: On average, x 1012 HCV virions are produced in each infected individual per day2
High mutation rate: The HCV polymerase lacks a proofreading function and is error prone3
Transition
The viral dynamics of HCV mean that a cure is possible.
Key Points
Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), HCV is curable
This is because HCV RNA remains in the cytoplasm and does not integrate into the host DNA1
HCV is highly genetically variable due to its:
High replication rate: On average, 1.3 × 1012 HCV virions are produced in each infected individual per day2
High mutation rate: The HCV polymerase lacks a proofreading function and is error prone3
References
Soriano V, et al. J Antimicrob Chemother. 2008;62:1-4.
Neumann AU, et al. Science. 1998;282:
Brown NA. Expert Opin Investig Drugs. 2009;18:
Host Cell
Nucleus
HBV=hepatitis B virus; HIV=human immunodeficiency virus; aCure, also known as SVR, is defined as no detectable HCV in the blood at 12 or more weeks after therapy is complete.4
Host DNA
Soriano V, et al. J Antimicrob Chemother. 2008;62:1-4.
Neumann AU, et al. Science. 1998;282:
Brown NA. Expert Opin Investig Drugs. 2009;18:
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.

9. Natural History of HCV Infection
14%- 46%
<1%
54%-86%
15%-51%
3%-6% per year
1%-5% per year
0.8% per yeara
Spontaneous clearance
Fulminant
hepatitis
Hepatocellular carcinoma (HCC)
Hepatic decompensation
Liver cirrhosis
Chronic hepatitis C
Acute HCV infection
Annual mortality rate of 2%-4% in CHC-infected patients with cirrhosis
Transition
This graphic shows the natural history HCV infection from acute infection to development of liver disease-related complications.
Key Points
Many patients with HCV infection remain undiagnosed for a long time due to a lack of liver-specific symptoms
After acute infection, approximately 54%-86% of patients progress to chronic infection, whereas only 14% to perhaps 46% experience spontaneous resolution
Among those with chronic HCV infection, approximately 15%-51% will develop cirrhosis
On average, cirrhosis develops in 16% of patients within 20 years after onset of HCV infection
Once cirrhosis has developed, a variable course is still observed: 3%-6% per year will experience hepatic decompensation, and approximately 1%-5% will develop hepatocellular carcinoma (HCC) annually
0.8% of those with CHC may develop HCC without having developed cirrhosis
The annual mortality rate for CHC patients with cirrhosis is 2%-4%
Reference
Maasoumy B, et al. Best Pract Res Clin Gastroenterol. 2012;26:
a0.8% of those with CHC may develop HCC without having developed cirrhosis.
Adapted from Maasoumy B, et al. Best Pract Res Clin Gastroenterol. 2012;26:

10. HCV GT 3 Is Associated With Fibrosis Progression and Risk of HCC
CHC typically is characterized by slowly progressing hepatic fibrosis1
GT 3 was associated with accelerated fibrosis progression2
Patients from the Swiss Hepatitis C Cohort Study enrolled before December 2008 (N=1189)
GT 3 was associated with an increased risk of developing HCC3
Retrospective study of patients in the VA HCV Clinical Case Registry, (N=110,484)
Cumulative Incidence of Fibrosis Progression
Year
Progression to Fibrosis Stage 1-22
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00 5 10 15 20 25 30 35 40
GT 1 or 4 (n=492, ref)
GT 2 (n=65, P=0.003)
GT 3 (n=244, P<0.001)
Year
Progression to Fibrosis Stage 3-42 5 10 15 20 25 30 35 40
GT 1 or 4 (n=630, ref)
GT 2 (n=92, P=0.04)
GT 3 (n=342, P<0.001)
Proportion Free of HCC
Incident HCC3
Year
N=110,484
Adjusted HRa=1.80 ( )
1.00
0.98
0.96
0.94
0.92
0.90
0.88
0.86
0.84
0.82
0.80
GT 1 (n=88,348)
GT 2 (n=13,077)
GT 3 (n=8337)
GT 4 (n=1082) 1 2 3 4 5 6 7 11 8 9 10
Transition
HCV GT 3 is associated with fibrosis progression and risk of cirrhosis and HCC.
Key Points
Chronic HCV infection typically is characterized by slowly progressing hepatic fibrosis1
The first 2 graphs in this slide show a significantly accelerated progression in GT 3 patients to fibrosis stage 1 or 2 or fibrosis stage 3 or 4 at first biopsy2
The graph on the far right shows that the risk of developing HCC was 80% greater in patients with GT 3 than in those with GT 1 (HR=1.80; 95% CI, )
Additionally, the risk of developing cirrhosis with GT 3 was 31% greater compared with GT 1 (HR=1.31; 95% CI, )3
Background
In the first study, patients were from the Swiss Hepatitis C Cohort Study (SCCS), a multicenter study carried out at 8 major Swiss hospitals and their affiliated centers (left and center graphs)2
Included in the study were 1189 CHC patients, who were entered in the database prior to December 2008 and who had at least one biopsy prior to antiviral treatment and accessible date of infection
The second study used data from the VA HCV Clinical Case Registry, which contains health information for all known HCV-infected patients from 128 Veterans Administration (VA) facilities nationwide (from 2000 to 2009) (far right graph)3
The study cohort included 110,484 patients with HCV who were followed for a mean of 5.4 years
References
McCaughan GW, et al. Gut. 2004;53:
Bochud PY, et al. J Hepatol. 2009;51:
Kanwal F, et al. Hepatology. 2014;60:
HR=hazard ratio; VA=Veterans Administration.
aHR for GT 3 compared to GT 1. Adjusted for pre-specified demographic, clinical, and treatment factors.3
McCaughan GW, et al. Gut. 2004;53:
Bochud PY, et al. J Hepatol. 2009;51:
Kanwal F, et al. Hepatology. 2014;60:

11. Module 2: Pre-treatment Assessment

12. HCV Testing Guidelines Recommend Age-Based and Risk-Based Screening
Current HCV screening guidelines from the CDC, USPSTF, and AASLD/IDSA recommend screening according to1-3:
Age
One-time screening of individuals born between 1945 and 1965 (e.g., baby boomers)
Risk factors
Past or current injection drug use
Additional risk factors include
Receiving a blood transfusion or organ transplant before 1992
Long-term hemodialysis
Being born to an HCV-infected mother
Incarceration
Intranasal drug use
Getting an unregulated tattoo, and other percutaneous exposures
HIV infection
Unexplained chronic liver disease
Transition
Current HCV screening guidelines from the CDC, USPSTF, and AASLD/IDSA recommend screening according to age and risk factors.1-3
Key Points
Looking at age:
One-time screening is recommended for all individuals born between 1945 and 1965 (baby boomers)
In addition, risk factors include:
Past or current injection drug use
Receiving a blood transfusion or organ transplant before 1992
Long-term hemodialysis
Being born to an HCV-infected mother
Incarceration
Intranasal drug use
Getting an unregulated tattoo, and other percutaneous exposures
HIV infection
Unexplained chronic liver disease
References
CDC. MMWR. 2012;61(No RR-4):1-31.
Moyer VA, et al; on behalf of the USPSTF. Ann Intern Med. 2013;159:
AASLD/IDSA. HCV testing and linkage to care. Accessed March 3, 2016.
AASLD/IDSA=American Association for the Study of Liver Diseases/Infectious Diseases Society of America; CDC=Centers for Disease Control and Prevention; USPSTF=US Preventive Services Task Force.
CDC. MMWR. 2012;61(No RR-4):1-31.
Moyer VA, et al; on behalf of the USPSTF. Ann Intern Med. 2013;159:
AASLD/IDSA. HCV testing and linkage to care. Accessed March 3, 2016.

13. Recommended Testing Sequence for HCV Screening and Diagnosis
HCV antibody test
STOPa
Nonreactive
No HCV antibody detected – +
Reactive
HCV RNA test
Not detected
No current HCV infection
Additional testing as appropriateb
Detected
Current HCV infection
Link to care
Transition
This schematic shows the recommended testing sequence for HCV screening and diagnosis from the CDC.
Key Points
If HCV antibody is nonreactive, no HCV antibody was detected
The sample can be reported as nonreactive for HCV antibody; no further action is required. If the patient may have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up HCV antibody testing is recommended
For persons who are immunocompromised, testing for HCV RNA can be considered
If HCV antibody is reactive, HCV infection is presumed
A repeatedly reactive result is consistent with current HCV infection, or past HCV infection that has resolved, or biologic false positivity for HCV antibody. Test for HCV RNA to identify current infection
If HCV antibody is reactive and HCV RNA is detected, the patient has current HCV infection
Provide person tested with appropriate counseling and link person tested to care and treatment. Before initiating antiviral therapy, it is recommended to retest for HCV RNA in a subsequent blood sample to confirm HCV RNA positivity
If HCV antibody is reactive, but HCV RNA is not detected, the patient is not currently infected with HCV
Follow-up HCV RNA testing may be considered if the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen
Reference
CDC. MMWR. 2013;62:1-4.
aFor persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered.
bTo differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.
Adapted from CDC. MMWR. 2013;62:1-4.

14. Recommended Assessment Prior to Starting Antiviral Therapy
Evaluation for advanced fibrosis using liver biopsy, imaging, and/or noninvasive markers
Facilitates an appropriate decision regarding HCV treatment strategy
Determines the need for additional measures for the management of patients with cirrhosis
Baseline laboratory testing (within 12 weeks prior to therapy initiation)
Complete blood count (CBC); international normalized ratio (INR)
Hepatic function panel and liver enzymes (albumin, total and direct bilirubin; alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase levels)
Calculated glomerular filtration rate (GFR)
If interferon (IFN) is to be used: Thyroid-stimulating hormone (TSH)
Any time prior to starting antiviral therapy
HCV genotype and subtype
Quantitative HCV RNA (viral load)
Evaluation of comorbidities
Screening for HBV and/or HIV-1 co-infection
Assess potential drug-drug interactions with concomitant medications
Including nontraditional treatments and herbal remedies
Transition
The guidance from the AASLD/IDSA panel recommends a number of pre-treatment assessments to help guide treatment decisions.
Key Points
An accurate assessment of fibrosis remains vital, because the degree of hepatic fibrosis is one of the most robust prognostic factors used to predict HCV disease progression and clinical outcomes
Assessing fibrosis facilitates an appropriate decision regarding HCV treatment strategy
It also determines the need for additional measures for the management of patients with cirrhosis
The AASLD/IDSA guidelines recommend the following baseline laboratory tests within 12 weeks prior to starting antiviral therapy:
Complete blood count (CBC); international normalized ratio (INR)
Hepatic function panel and liver enzymes (albumin, total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase levels)
Calculated glomerular filtration rate (GFR)
If interferon (IFN) is to be used: Thyroid-stimulating hormone (TSH)
The following tests are recommended any time prior to starting antiviral therapy
HCV genotype and subtype
Quantitative HCV RNA (viral load)
Evaluation of comorbidities
Screening for HBV and/or HIV-1 co-infection
Assess potential drug-drug interactions with concomitant medications
Including nontraditional treatments and herbal remedies
Reference
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.

15. Baseline Fibrosis Assessment Is Important for Developing a Chronic HCV Treatment Plan
Accurate assessment of fibrosis is recommended for all patients with CHC to determine appropriate treatment strategy and follow-up1
Patients with severe fibrosis require surveillance monitoring for liver cancer, esophageal varices, and hepatic function
Although liver biopsy is the diagnostic standard, the most efficient approach is to combine direct biomarkers and vibration-controlled transient liver elastography1
A biopsy should be considered for any patient with discordant results between the 2 methods that would affect clinical decision making
If direct biomarkers or elastography are not available, APRI or FIB-4 tests can help, although neither test is sensitive enough to rule out substantial fibrosis1
Cirrhosis may be significantly underdiagnosed and underdocumented in patients with CHC2
Individuals with clinically evident cirrhosis do not require additional staging1
Transition
According to current treatment guidelines, baseline assessment of fibrosis is an important part of developing a CHC treatment plan.
Key Points
Accurate assessment of fibrosis is recommended for all patients with CHC to determine appropriate treatment strategy and follow-up
Patients with severe fibrosis require surveillance monitoring for liver cancer, esophageal varices, and hepatic function
Although liver biopsy is the diagnostic standard, the most efficient approach is to combine direct biomarkers and vibration-controlled transient liver elastography
A biopsy should be considered for any patient with discordant results between the 2 methods that would affect clinical decision making
If direct biomarkers or elastography are not available, APRI or FIB-4 tests can help, although neither test is sensitive enough to rule out substantial fibrosis
Cirrhosis may be significantly underdiagnosed and underdocumented in patients with CHC2
Individuals with clinically evident cirrhosis do not require additional staging1
References
AASLD/IDSA. When and in whom to initiate HCV therapy. whom-initiate-hcv-therapy. Accessed March 3, 2016.
Gordon S, et al. Am J Gastroenterol. 2015;110:
APRI=AST-to-platelet ratio index; FIB-4=fibrosis 4.
AASLD/IDSA. When and in whom to initiate HCV therapy. Accessed March 3, 2016.
Gordon S, et al. Am J Gastroenterol. 2015;110:

16. Comparing Invasive and Noninvasive Fibrosis Tests
Liver Biopsy
Methodology
Direct observation
Accuracy for detecting cirrhosis
High
Accuracy for detecting intermediate fibrosis
Risk of complications
Risk of pain/bleeding
Contraindications
Coagulopathy
Limitations
Sampling error
Observer variation
Longitudinal monitoring
Unsuitable
Cost
Highest per-test cost
Serum Markers
Measures direct and indirect serum markersa of fibrosis
Moderate (APRI) to high (FibroSureTM, ELF)
Low (APRI) to moderate (FibroSureTM, ELF)
Minimal
False-positives with hemolysis, inflammation, Gilbert’s syndrome
Indices may change with disease progression/ therapy
Low per-test cost
Transient Elastography
Measures liver stiffness by detection of ultrasound-propagated shear waves
High
Moderate to high
Minimal
Accuracy lessened with obesity and/or narrow rib spaces
False-positives with inflammation, congestion
Liver stiffness changes with disease progression/ therapy
High initial equipment cost
MRE
Measures liver stiffness by MRI of vibration-propagated shear waves
High
Minimal
Claustrophobia; other MRI contraindications
False-positives with inflammation, congestion
Liver stiffness changes with disease progression/therapy
Very high initial equipment cost
Transition
This table provides an overview of the available invasive and noninvasive fibrosis tests.
Key Points
A variety of serum markers have been developed for identifying patients who are at risk for clinically significant hepatic fibrosis (defined by stages F2-F4)
These markers are classified as direct (representing components of extracellular matrix) or indirect (reflecting hepatic inflammation and function). Indirect markers may be used alone or combined with direct markers to form panels
The practical advantages of serum fibrosis markers include their noninvasiveness, potential for widespread availability, and reproducibility when serial examinations are performed using the same laboratory
Reference
Nguyen D, Talwalkar JA. Hepatology. 2011;53:
ELF=enhanced liver fibrosis; MRE=magnetic resonance elastography, MRI=magnetic resonance imaging.
aSerum tests that incorporate markers of fibrogenesis are generally more accurate.
Nguyen D, Talwalkar JA. Hepatology. 2011;53:

17. Extrahepatic Manifestations of HCV
Mixed cryoglobulinemia
Sjögren (sicca) syndrome
Lymphoproliferative disorders
Porphyria cutanea tarda
Neuropathy
Membranoproliferative glomerulonephritis
Cryoglobulinemic (leukocytoclastic) vasculitis
Strongly associated1
Corneal ulcers (Mooren’s ulcer)
Thyroid disease
Lichen planus
Pulmonary fibrosis
Chronic kidney disease
Type 2 diabetes
Systemic vasculitis (polyarteritis nodosa, microscopic polyangiitis)
Arthralgias, myalgias, inflammatory polyarthritis
Autoimmune thrombocytopenia
Neurocognitive dysfunction
Possibly associated1-3
Transition
Chronic HCV is a systemic disease that impacts the overall health of the patient.
Key Points
This slide shows extrahepatic manifestations that have been strongly associated with HCV, as well as those possibly associated with HCV1-3
Extrahepatic manifestations can complicate HCV infection. Some of the manifestations are strongly associated with HCV; others are not as strongly associated
In a Toronto study (N=79) of neurocognitive dysfunction in HCV-infected patients without other risk factors, patients who did not respond to HCV treatment had a significantly lower mean score at baseline (before treatment) on the California Verbal Learning Test II when compared with uninfected controls (P=0.012)
References
Ali A, Zein NN. Cleve Clin J Med. 2005;72:
Satapathy SK, et al. Hepatol Int. 2012;6:
Pattullo V, et al. Liver Int. 2011;31:
Adapted from Ali A, Zein NN.
Ali A, Zein NN. Cleve Clin J Med. 2005;72:
Satapathy SK, et al. Hepatol Int. 2012;6:
Pattullo V, et al. Liver Int. 2011;31:

18. Common Comorbidities Diagnosed in Chronic HCV Patients: 2005-2009
Several comorbidities, such as lymphoma, type 2 diabetes mellitus, and renal manifestations, have been shown to be associated with CHC1
A cross-sectional, retrospective analysis of the US National Inpatient Sample (NIS) identified comorbidities commonly diagnosed in hospitalized CHC patients between 2005 and 20092
Comorbidities as Primary or Secondary Diagnoses for Hospitalized CHC Patients2
P<0.001
P=0.019
P=0.003
Comorbidity Diagnoses (%) a b .
Transition
Several comorbidities have been shown to be associated with CHC.
Key Points
Several comorbidities, such as lymphoma, type 2 diabetes mellitus, and renal failure, have been shown to be associated with CHC1
A recent cross-sectional, retrospective analysis of the National Inpatient Sample (NIS) reported diagnoses of comorbidities and complications in CHC patients in the United States between 2005 and 20092
Comorbidities increased significantly suggesting that these patients became sicker with time
Diagnoses of coagulopathy, cancer (metastatic cancer, solid tumor without metastasis, lymphoma), and renal failure almost doubled between 2005 and 2009 in hospitalized HCV patients
Background
The study was based on hospital discharge records for adults 20+ years old between 2005 and with ICD-9 codes for HCV with or without liver complications2
Data were from the NIS, which is the largest all-payer database for hospitalizations in the United States, accounting for more than 8 million hospital discharges
The National Hospital Discharge Survey was used for comparative analysis
References
Zignego AL, et al. Intern Emerg Med. 2012;7:S201-S208.
Younossi ZM, et al. J Viral Hepat. 2015;22: . .
P values reported by linear trend and chi-square test.
aChronic pulmonary disease and pulmonary circulation disorder. bMetastatic cancer, solid tumor without metastasis, lymphoma.
Zignego AL, et al. Intern Emerg Med. 2012;7:S201-S208.
Younossi ZM, et al. J Viral Hepat. 2015;22:

19. HCV Infection May Be Complicated by a Wide Range of Comorbidities
Proportion of CHC Cases and Uninfected Controls Reporting Comorbidities
in a Retrospective Study
Patients (%)
Number of Comorbidities Reported
Transition
HCV may be associated with a wide range of comorbidities.
Key Points
A retrospective cohort study of CHC patients within a US medical claims database showed that comorbidities were common in HCV-infected patients. Only 41 out of 7411 patients (0.6%) reported no comorbidities
Nearly 80% of CHC patients reported at least 6 comorbidities
When comparing HCV-infected patients to HCV-uninfected controls, HCV-infected patients reported almost double the number of comorbidities (101,219 vs 53,589, respectively)
The findings of the study showed that HCV is a systemic infection involving a wide range of comorbidities
The most prevalent extrahepatic comorbidities associated with HCV infection seen in the study population included rheumatoid symptoms (within connective tissue disease and malaise/fatigue) and psychological disorders (within substance-related mental disorders and depressive disorders)
Common symptoms associated with HCV disease seen in the study population included abdominal pain, joint pain (including back problems and joint disorders), gastrointestinal disorders (comprising diarrhea, splenomegaly, irritable bowel syndrome and unspecified site of abdominal/pelvic swelling), nonspecific chest pain and disorders of lipid metabolism
These comorbidities may complicate HCV prognosis, management, and treatment
Background
This study was based on data from US medical claims from the Integrated Health Care Information System (IHCIS) National Benchmark database, which contains claims and patient diagnosis information from more than 30 healthcare plans in 8 census regions
The evaluation of data from CHC patients (claims from November 1998 to May 2006) was designed to estimate the prevalence of comorbidities over a 2-year period
Patients were included if they had 2 HCV diagnosis codes, 24 months of continuous health insurance coverage, and full medical and pharmacy benefits (N=7411)
Controls were enrollees without HCV randomly selected from the IHCIS. They were matched to an HCV-infected case by age, sex, continuous medical health coverage, and enrollment period
Reference
Louie KS, et al. BMC Infect Dis. 2012;12:86.
Nearly 80% of CHC patients reported ≥6 comorbidities
CHC patients reported nearly double the number of comorbidities compared with uninfected controls
Data based on analysis of US medical claims (N=7411) from the Integrated Health Care Information System (IHCIS) National Benchmark database, from >30 healthcare plans in 8 census regions (claims from November 1998 to May 2006).
Adapted from Louie KS, et al. BMC Infect Dis. 2012;12:86.

20. Select Host Factors Associated With More Rapid Disease Progression
Nonmodifiable Host Factors
Older age at infection
Associated with accelerated cirrhosis development1
Increasing age (longer duration of infection)
Associated with accelerated fibrosis progression1
Hispanic ethnicity
Higher mortality rates from HCV-related cirrhosis2
Hispanic ethnicity is an independent risk factor for HCC-related mortality3
Genetic factors
African Americans have lower histologic activity and incidence of liver cirrhosis than Caucasians4
Behavioral and Clinical/Laboratory Host Factors
Increased severity of alcohol usea
Associated with significant risk of advanced hepatic fibrosis5
Combined obesity and diabetes mellitus
Associated with 100-fold increase in risk of HCC development6
↑ AST/ALT ratio, ↑ bilirubin, ↓ albumin, and ↓ platelet count
Independent predictors of fibrosis progression or clinical decompensation7
HCV GT 3 infection
Associated with increased risk of cirrhosis and HCC8
HIV-1 co-infection
Associated with higher viral load, rapid progression to cirrhosis, liver failure, and HCC9
HBV co-infection
Associated with increased risk of HCC10
Transition
The course of chronic HCV infection is influenced by a number of nonmodifiable and modifiable risk factors.1-10
Key Points
It is important to consider the contribution of individual nonmodifiable risk factors when determining personalized HCV treatment approaches. These include:
Older age at infection
Increasing age (i.e., longer duration of infection)
Hispanic ethnicity
Genetic factors (i.e., Caucasian)
Additional factors that may affect disease progression include the behavioral and clinical factors listed here:
Increased severity of alcohol consumption
The combination of obesity and diabetes mellitus
Platelet counts, AST/ALT ratio, bilirubin and albumin levels
Infection with HCV GT 3, in US Veterans
Co-infection with either HIV-1 or HBV (community-based prospective cohort study conducted in Korea between )
References
Malnick S, et al. Drugs Aging. 2014;31:
Yoon YH, et al. Alcohol Clin Exp Res. 2011;35:
Younossi ZM, Stepanova M. Clin Gastroenterol Hepatol. 2010;8:
Maasoumy B, Wedemeyer H. Best Pract Res Clin Gastroenterol. 2012;26:
Lim JK, et al. Clin Infect Dis. 2014;58:
Goossens N, Negro F. Clin Liver Dis. 2014;18:
Ghany MG, et al. Gastroenterology. 2010;138:136.
Kanwal F, et al. Hepatology. 2014;60:
Kang W, et al. Expert Rev Gastroenterol Hepatol. 2014;8:
Oh JK, et al. BMC Cancer. 2012;12:452.
aIncreasing alcohol use categories defined as nonhazardous drinking, hazardous or binge drinking, and alcohol-related diagnosis.5
Malnick S, et al. Drugs Aging. 2014;31:
Yoon YH, et al. Alcohol Clin Exp Res. 2011;35:
Younossi ZM, Stepanova M. Clin Gastroenterol Hepatol. 2010;8:
Maasoumy B, Wedemeyer H. Best Pract Res Clin Gastroenterol. 2012;26:
Lim JK, et al. Clin Infect Dis. 2014;58:
Goossens N, Negro F. Clin Liver Dis. 2014;18:
Ghany MG, et al. Gastroenterology. 2010;138:136.
Kanwal F, et al. Hepatology. 2014;60:
Kang W, et al. Expert Rev Gastroenterol Hepatol. 2014;8:
Oh JK, et al. BMC Cancer. 2012;12:452.

21. Module 3: Managing HCV Therapy

22. HCV Treatment Advances Through the Years
Hepatitis C
discovered1
1991
1998
2001
2011
IFN approved2
Peginterferon alfa (Peg-IFN) approved2
Direct-acting antiviral agents (DAA) approved3
Ribavirin (RBV) approved2
IFN-free therapies approved3
1989
2013-present
Transition
This timeline shows the progress of HCV treatment over the past few decades.
Key Points
Since the discovery of hepatitis C in 1989, there has been a rapid advancement in treatment options1-3
Recent advances in therapeutic options now provide high cure rates (>90%) with direct-acting antiviral (DAA) options that are IFN-free3
References
CDC. Hepatitis C: 25 Years of Discovery. Accessed June 25, 2015.
Franciscus A. Interferon, ribavirin & HCV protease inhibitors. HCV Advocate site. March 2012.
FDA. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment Guidance for Industry. Accessed May 13, 2016.
Recent advances in HCV therapeutic options provide high cure rates (>90%) with direct-acting antiviral options that are IFN-free3
CDC. Hepatitis C: 25 Years of Discovery. Accessed June 25, 2015.
Franciscus A. Interferon, ribavirin & HCV protease inhibitors. HCV Advocate site. March 2012.
FDA. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment Guidance for Industry. Accessed May 13, 2016.

23. Improvements in HCV Therapy: Overall SVR Rates in the Pre-DAA and DAA Eras
Standard of Care
Overall SVRa Rates
Pre-2011
(Pre-DAA)
Peg-IFN + RBV
47%-54%1,2
aSVR=24-week follow-up
(Early DAA)
DAA + Peg-IFN + RBV
67%-75%3,4
2013-present
(all-oral DAA regimens)
DAA regimen ± RBV
≥90%5-9
aSVR=12-week follow-up
Transition
There have been substantial improvements in the potential for antiviral therapy to result in SVR (virologic cure).
Key Points
This table provides an overview of the improvements in SVR rates in the pre-DAA and DAA eras
Prior to 2011, the standard of care was peginterferon alfa (Peg-IFN) + ribavirin (RBV). This regimen offered SVR rates in the range of 47%-54%1,2
With the early DAAs, Peg-IFN and RBV were still required, but overall SVR rates improved to 67%-75%3,4
Current DAA regimens are available that can be used with or without RBV. The new therapies offer SVR rates at or above 90% for most patients5-9
References
Manns MP, et al. Lancet. 2001;358:
Fried MW, et al. N Engl J Med. 2002;347:
Poordad F, et al. N Engl J Med. 2011;364:
Jacobson IM, et al. N Engl J Med. 2011;364:
Lawitz E, et al. N Engl J Med. 2013;368:
Ferenci P, et al. N Engl J Med. 2014;370:
Afdhal N, et al. N Engl J Med. 2014;370:
Feld JJ, et al. N Engl J Med. 2015;373:
Foster GR, et al. N Engl J Med. 2015;373:
Manns MP, et al. Lancet. 2001;358:
Ferenci P, et al. N Engl J Med. 2014;370:
Fried MW, et al. N Engl J Med. 2002;347:
Afdhal N, et al. N Engl J Med. 2014;370:
Poordad F, et al. N Engl J Med. 2011;364:
Feld JJ, et al. N Engl J Med. 2015;373:
Jacobson IM, et al. N Engl J Med. 2011;364:
Foster GR, et al. N Engl J Med. 2015;373:
Lawitz E, et al. N Engl J Med. 2013;368:

24. HCV Treatment Goals
Achieve SVR (virologic cure) − defined as the absence of detectable HCV RNA for ≥12 weeks after completion of therapy (i.e., SVR12)
Clinical improvement
Reduce all-cause mortality
Reduce liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma
Transition
This slide highlights the overall goals of HCV treatment.
Key Points
The proximate goal of HCV therapy is SVR (virologic cure), defined as the continued absence of detectable HCV RNA at least 12 weeks after completion of therapy. SVR is a marker for cure of HCV infection and has been shown to be durable, in large prospective studies, in more than 99% of patients followed up for 5 years or more
Patients in whom an SVR is achieved have HCV antibodies but no longer have detectable HCV RNA in serum, liver tissue, or mononuclear cells, and achieve substantial improvement in liver histology
Clinical improvement−Patients who are cured of their HCV infection experience numerous health benefits, including:
Reduced all-cause mortality
Reduced liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma
Reference
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.

25. Principles of Monitoring Patients on Antiviral Treatment
While on treatment, patients should be monitored at intervals sufficient to ensure safety and response to treatment
Clinic visits or telephone follow-ups are recommended to ensure medication adherence and monitor for adverse events and potential drug-drug interactions
CBC, creatinine level, calculated GFR, and hepatic function panel monitoring are recommended after 4 weeks of therapy and as clinically indicated
Measure quantitative HCV viral load after 4 weeks of therapy and at 12 weeks after completion of treatmenta
Antiviral drug therapy should NOT be interrupted or discontinued if HCV RNA levels are not performed or available during treatment
If HCV RNA is detectable at Week 4, repeat quantitative HCV RNA testing is recommended after an additional 2 weeks of therapy
If HCV viral load has increased by >10-fold on repeat testing at ≥Week 6, discontinuation of HCV treatment is recommended
Quantitative HCV viral load testing can be considered at the end of treatment and 24 weeks or longer following the completion of therapy
Transition
The treatment guidelines from the AASLD and IDSA provide recommendations on how to monitor patients who decide to initiate antiviral therapy.
Key Points
The guidance from the AASLD/IDSA panel recommends monitoring patients while on antiviral therapy to ensure medication adherence, assess adverse events and potential drug-drug interactions, and monitor blood test results necessary for patient safety.
Clinic visits or telephone follow-ups are recommended to ensure medication adherence, monitor for adverse events, and potential drug-drug interactions
Monitoring CBC, creatinine level, calculated GFR, and hepatic function is recommended after 4 weeks of therapy and as clinically indicated
Measure quantitative HCV viral load after 4 weeks of therapy and at 12 weeks after completion of treatment
Antiviral drug therapy should NOT be interrupted or discontinued if HCV RNA levels are not performed or available during treatment
If HCV RNA is detectable at Week 4, repeat quantitative HCV RNA testing is recommended after an additional 2 weeks of therapy
If HCV viral load has increased by >10-fold on repeat testing at ≥Week 6, discontinuation of HCV treatment is recommended
Quantitative HCV viral load testing can be considered at the end of treatment and 24 weeks or longer following the completion of therapy
Reference
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.
aAssessment of HCV viral load at Week 4 of therapy is useful to determine initial response to therapy and adherence.
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.

26. Module 4: Post-treatment Follow-up

27. Potential Benefits of SVR (Virologic Cure)
Achieving SVR is associated with reduced medical costs when compared with patients who do not achieve SVR1,a
Achieving SVR is associated with reductions in HCC, liver-related mortality or transplantation, and all-cause mortality2,a
Achieving SVR may lower the incidence of HCV-related comorbidities3-6,a
Achieving SVR may improve relevant aspects of attentional and neurocognitive performance7,a
In a real-world cross-sectional study, SVR was associated with certain improved quality-of-life measurements8,a
Regression of cirrhosis and fibrosis are frequently observed in patients with cirrhosis who achieve long-term SVR (median period of 61 months)9
Transition
As shown in the following slides, achieving SVR is associated with numerous clinical and economic benefits.
Key Points
Achieving SVR is associated with reduced medical costs when compared with patients who do not achieve SVR1
Achieving SVR is associated with reductions in HCC, liver-related mortality or transplantation, and all-cause mortality2
Achieving SVR may lower the incidence of HCV-related comorbidities3-6
Neurocognitive function improves in patients with CHC following SVR7
Among responders, neurocognitive performance was significantly improved in TAP (Test for Attention Performance) subtasks related to vigilance, divided attention (optical), and working memory compared with baseline evaluation
In a real-world cross-sectional study, SVR was associated with certain improved quality of life measurements8
One of the limitations of this study was that there was no assessment of quality of life prior to antiviral therapy
Regression of cirrhosis and fibrosis are frequently observed in patients with cirrhosis who achieve long-term SVR (median period of 61 months)9
References
Manos MM, et al. J Managed Care Pharmacy. 2013;19:
van der Meer AJ, et al. JAMA. 2012;308:
Arase Y, et al. Hepatology. 2009;49:
Arase Y, et al. J Med Virol. 2014;86:
Arcaini L, et al. Ann Oncol. 2014;25:
Hsu YC, et al. Hepatology. 2014;59:
Kraus MR, et al. Hepatology. 2013;58:
John-Baptiste AJ, et al. Am J Gastroenterol. 2009;104:
D’Ambrosio R, et al. Hepatology. 2012;56:
aSVR was defined as lack of detection of HCV RNA at 24 weeks after the cessation of treatment.
Manos MM, et al. J Managed Care Pharmacy. 2013;19:
Hsu YC, et al. Hepatology. 2014;59:
van der Meer AJ, et al. JAMA. 2012;308:
Kraus MR, et al. Hepatology. 2013;58:
Arase Y, et al. Hepatology. 2009;49:
John-Baptiste AJ, et al. Am J Gastroenterol. 2009;104:
Arase Y, et al. J Med Virol. 2014;86:
D’Ambrosio R, et al. Hepatology. 2012;56:
Arcaini L, et al. Ann Oncol. 2014;25:

28. SVR Associated With Reduced Medical Costs Post-treatment
Rate Ratios for Costs by Post-treatment Year:
Healthcare Costs Higher Among Non-SVR Group Compared With SVR Groupa
P=0.9b
Hospital
10.00
1.00
Adjusted Rate Ratio (95% CI)
Category of Cost ($)
P=0.68b
Total
1.26
1.44
1.64
1.41
1.46
1.47
1.59
2.1
2.08
1.10
P=0.11b
Outpatient Nonpharmacy
1.18
1.31
1.3
1.08
P=0.26b
Outpatient Pharmacy
1.16
1.45
1.77
1.84
Year 1
Year 2
Year 3
Year 4
Year 5
Higher cost among non-SVR group
Transition
According to a retrospective analysis looking at healthcare utilization, patients without SVR incurred significantly higher healthcare costs than patients with SVR.
Key Points
For each post-treatment year, total adjusted costs were significantly higher in the non-SVR group than in the SVR group, with rate ratios (RRs) and 95% CIs ranging from 1.26 (95% CI, ) to 1.64 (95% CI, ), driven mostly by hospital and outpatient pharmacy costs
When all post-treatment years were considered collectively, the non-SVR group had significantly higher costs overall (RR=1.41; 95% CI, )
Background
SVR was defined as lack of detection of HCV RNA at 24 weeks after the cessation of treatment
This retrospective analysis included 1924 patients who received HCV treatment with Peg-IFN and RBV between 2002 and 2007
Healthcare utilization and costs for up to 5 years after treatment completion were derived from electronic records
The mean duration of post-treatment time was 3 years
Reference
Manos M, et al. JMCP. 2013;19:
When all post-treatment years were considered collectively, the non-SVR group had significantly higher costs overall (RR=1.41; 95% CI, )
SVR was defined as lack of detection of HCV RNA at 24 weeks after the cessation of treatment.
aRate ratios of non-SVR group relative to SVR group graphed on logarithmic scale. Values above each bar represent the rate ratio. Bars represent 95% CIs.
bP values for test of heterogeneity over time in association between SVR and costs.
Adapted from Manos M, et al. JMCP. 2013;19:

29. Cumulative Incidence (%)
SVR Associated With a Reduction in HCC, Liver-Related Mortality, Transplantation, and All-Cause Mortality 30 20 10
Cumulative Incidence (%)
Without SVR
With SVR 1 2 3 4 5 6 7 8 9
Time (y)
Hepatocellular Carcinoma
Liver-Related Mortality or Liver Transplantation
Without SVR
With SVR 1 2 3 4 5 6 7 8 9 10
Time (y)
All-Cause Mortality
Without SVR
With SVR 1 2 3 4 5 6 7 8 9 10
Time (y)
P <0.001
P <0.001
P <0.001
This was an international, multicenter, long-term follow-up study of 530 consecutive CHC patients with advanced hepatic fibrosis or cirrhosis (Ishak score 4-6), who started an IFN-based treatment regimen between 1990 and 2003, from 5 large tertiary care hospitals in Europe and Canada. Complete follow-up occurred between January 2010 and October Median follow-up duration was 8.4 years.
An international follow-up study of CHC patients with advanced hepatic fibrosis or cirrhosis showed significant reduction of 10-year cumulative incidence of HCC, liver-related mortality or transplantation, and all-cause mortality in patients who achieved SVR
SVR was defined as lack of detection of HCV RNA at 24 weeks after the cessation of treatment.
van der Meer AJ, et al. JAMA. 2012;308:
Transition
This slide shows that achieving SVR was associated with reductions in HCC incidence, liver-related or transplantation mortality, and all-cause mortality.
Key Point
In patients who achieved SVR, the 10-year cumulative incidences of HCC, liver-related mortality or liver transplant, and all-cause mortality were significantly reduced
Multivariable analysis also showed that SVR was associated with statistically significant reduction in the hazard of HCC (HR=0.19; P<0.001), all-cause mortality (HR= ; P<0.001), and liver-related mortality or liver transplant (HR=0.06; P<0.001)
Background
SVR was defined as lack of detection of HCV RNA at 24 weeks after the cessation of treatment
This was an international, multicenter, long-term follow-up study from 5 large tertiary-care hospitals in Europe and Canada of 530 patients with CHC and advanced hepatic fibrosis or cirrhosis (Ishak score 4-6), who started an IFN-based treatment regimen between 1990 and 2003
Completed follow-up occurred between January 2010 and October 2011 (median follow-up was 8.4 years)
Reference
van der Meer AJ, et al. JAMA. 2012;308:

30. SVR May Lower Cumulative Incidences of HCV-Related Comorbidities
Two retrospective studies in Japan showed that SVR reduced the cumulative incidences of type 2 diabetes mellitus1 and hemorrhagic stroke2
Cumulative Incidence (%)
Non-SVR/SVR
HRa=2.78 ( ); P<0.001 40 30 20 10
Non-SVR (N=1667)
SVR (N=1175)
Follow-up (y)
P<0.001
Type 2 Diabetes1
HCV nonclearance/clearance HRa=3.22 ( ); P=0.018
Cumulative Incidence (%) 8 6 4 2 10 30
HCV nonclearance
(N=2577)
HCV clearance (N=2125)
Follow-up (y)
P=0.020 20
0.4%
0.1%
1.1%
2.0%
Hemorrhagic Stroke2
Transition
This slide presents data from 2 studies demonstrating that achieving SVR may reduce HCV-related comorbidities, such as type 2 diabetes mellitus and hemorrhagic stroke.
Key Point
Cumulative incidences of some HCV-associated comorbidities have been shown to benefit from treatment1-4
Background
HCV clearance was defined as clearance of HCV RNA at 6 months after the cessation of therapy
The 2 studies were retrospective cohort studies in HCV-positive subjects conducted by the Department of Hepatology, Toranomon Hospital, Tokyo, Japan1,2
The first study included 2842 HCV-positive subjects who were treated with IFN monotherapy or IFN plus RBV combination therapy between 1990 and 20071
The cumulative incidence of type 2 diabetes was 3.6%, 8%, and 17% at 5, 10, and 15 years, respectively
However, non-SVR was shown to be an independent risk factor for type 2 diabetes (HR=2.78; P<0.001), while SVR was associated with a two-thirds reduction in the cumulative incidence of type 2 diabetes
The second study included 4649 HCV-positive subjects who were treated with IFN monotherapy or IFN plus RBV combination therapy between 1990 and 20102
The cumulative incidence of hemorrhagic stroke was 0.3%, 0.8%, and 1.7% at 5, 10, and 15 years, respectively
The cumulative incidence of hemorrhagic stroke was significantly lower in subjects with HCV clearance, as compared with those with HCV nonclearance
HCV nonclearance was associated with hemorrhagic stroke (HR=3.22; P=0.018)
References
Arase Y, et al. Hepatology. 2009;49:
Arase Y, et al. J Med Virol. 2014;86:
Arcaini L, et al. Ann Oncol. 2014;25:
Hsu YC, et al. Hepatology. 2014;59:
Antiviral treatment has shown benefit for other comorbidities, such as lymphoma,3 end-stage renal disease,4 and ischemic stroke4
Patient cohorts from the Toranomon Hospital, Japan: 2842 CHC patients were treated with an IFN-based regimen between September 1990 and March 20071; 4649 CHC patients were treated between September 1990 and May
HCV clearance was defined as clearance of HCV RNA at 6 months after the cessation of therapy. aCox regression analysis.
Arase Y, et al. Hepatology. 2009;49:
Arcaini L, et al. Ann Oncol. 2014;25:
Arase Y, et al. J Med Virol. 2014;86:
Hsu YC, et al. Hepatology. 2014;59:

31. Neurocognitive Function Has Been Demonstrated to Improve in Patients With Chronic HCV Following SVR
Divided Attention
(performance on optical tasks)b
Working Memory
(continuous flow of information with short-term memory)
Following SVR, HCV patients have been shown to have significantly improved cognitive function across several areas of assessment.a
Vigilance
(sustained attention)
Transition
Neurocognitive function has been demonstrated to improve in patients with chronic HCV following SVR.
Key Points
A cognitive function study (N=168) completed in Germany has shown that patients (without decompensated liver disease or hepatocellular carcinoma) who achieve SVR show improvement in a number of key cognitive functions, including divided attention (performance on dual [optical] tasks), vigilance (sustained attention), and working memory (continuous flow of information with short-term memory)
Achieving SVR may alleviate some of the cognitive comorbidities patients complain about but do not necessarily associate with HCV (e.g., “brain fog”)
Background
SVR was defined as lack of detection of HCV RNA at 24 weeks after the cessation of treatment
The primary endpoint was the neurocognitive performance of the patients in each subgroup (SVR versus no SVR) 48 weeks after the end of the antiviral combination therapy
Reference
Kraus MR, et al. Hepatology. 2013;58:
SVR was defined as lack of detection of HCV RNA at
24 weeks after the cessation of treatment.
Patients were excluded if they had decompensated liver
disease or HCC.
aPatients were assessed by computerized Test of Attentional Performance (TAP).
bComparison between baseline and long-term follow-up evaluation 1 year after the end of antiviral treatment.
Kraus MR, et al. Hepatology. 2013;58:

32. Mean Difference in Scores (SVR vs Treatment Failure)
Real-World Clinic Population: SVR Was Associated With Improved Quality of Life Compared With Treatment Failures
A cohort study of community patients from 5 healthcare settings in Vancouver has shown that sustained responders reported higher scores than treatment failures on each domain of the SF-36 and on utility measures
SF-36 Scales
Mean Difference in Scores (SVR vs Treatment Failure)
aP<0.0001; bP<0.001; cP<0.01
Transition
This slide shows that achieving SVR may improve quality-of-life scores.
Key Point
Patients who achieved SVR 24 weeks after treatment ended reported significantly higher scores than treatment failures on all domains of the SF-36
Background
Sustained responders = undetectable HCV viral levels 6 months after therapy
This analysis was based on a cross-sectional administration of questionnaires and on a retrospective review of medical records. It was part of a larger study examining the quality-of-life burden of HCV in a community-dwelling population
A convenience sample was made up of 657 CHC patients from 5 healthcare settings in Vancouver, British Columbia, who were treated from Of these, 235 subjects were included in the analysis (133 responders and 102 treatment failures)
After adjustment for age, sex, ethnicity, marital status, education, Charlson comorbidity, and Index of Coexistence Disease scores using multivariable linear regression, SVR was significantly associated with higher SF-36 score (0.05; 95% confidence interval [CI], ), physical summary score (5.73; 95% CI, ), and mental summary score (5.22; 95% CI, )
The study has several limitations. Awareness of viremia status has been associated with decreased quality of life, but there were no data to indicate whether these patients were aware of their viremia status. There are no data indicating a higher patients' quality of life prior to antiviral therapy
Reference
John-Baptiste AJ, et al. Am J Gastroenterol. 2009;104:
This analysis was part of a larger study examining the quality of life and economic burden of HCV in community patients recruited between January 1, 2006, and March 1, 2008, in Vancouver, British Columbia, and included a cross-sectional administration of questionnaires with retrospective review of medical records. Of these, 235 patients (133 responders and 102 treatment failures) completed questionnaires at an average of 3.7 years after the end of treatment. Patients with advanced liver disease were excluded.
Sustained responders=undetectable HCV viral levels 6 months after therapy; treatment failures=detectable HCV viremia after therapy, or patients with an end-of-treatment response who relapsed.
MCS=mental component summary score (0-100); PCS=physical component summary score (0-100).
John-Baptiste AJ, et al. Am J Gastroenterol. 2009;104:

33. Cirrhosis Regression and Fibrosis Reduction Following SVR
Cirrhosis Regression in 61% of Patients
Sample Liver Biopsy
Pre-treatment (F4)
Post-treatment (F3) 2
Transition
In this prospective study, the dynamics of liver fibrosis were explored in patients with cirrhosis after long-term SVR.
Key Point
Cirrhosis regression and decreased fibrosis are frequently observed among HCV patients with cirrhosis with an SVR
Background
Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy ( ) to assess the impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis
4-year follow-up post-SVR
Exclusion: HIV or HBV, drug dependence, elevated alcohol intake, age >75 years
Patients received either Peg-IFN/RBV (74%) or IFN/RBV (26%)
Patients were followed up for a median of 67 months (range, months) after the end of treatment, the median interval between pre- and post-treatment liver biopsies being 79 months (range, months)
Study endpoints: Fibrosis/cirrhosis regression rates on paired liver biopsies; necro-inflammation; and progenitor cell proliferation, lobular metabolic zonation, sinusoidal capillarization
Median follow-up was 67 months
Results
All patients were F4 at baseline, using METAVIR staging. 23/38 patients (61%) showed an improvement of at least one point in METAVIR fibrosis stage
Histology images are from a patient with cirrhosis (F4) at baseline (pre-treatment). Nodular fibrosis with thick septa and nodular organization or hepatocytes is obvious. Second image is post-treatment liver biopsy from the same patient, now stage F3, showing still either incomplete or very thin septa
SVR was associated with decreased area of fibrosis in 34/38 patients (89%), as measured by digitizing Sirius Red staining of biopsy specimens
Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a median individual decrease of 71.8%
Reference
D’Ambrosio R, et al. Hepatology. 2012;56:
Fibrosis Reduction
After treatment, the area of fibrosis decreased in 34/38 (89%) of patients
Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a median individual decrease of 71.8%
Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy (enrolled in ) to assess the impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis. N=38, median f/u 67 months (range, months). Adapted from D’Ambrosio R, et al. Hepatology. 2012;56:

34. Post-treatment Monitoring for Patients Who Fail to Achieve SVR
Recommended follow-up for patients who do not achieve an SVR
Patients who do not achieve an SVR have ongoing HCV infection and risk continued liver injury and transmission
They should be monitored for disease progression every 6 to 12 months
Hepatic function panel, CBC, INR
For patients with cirrhosis, screening for esophageal varices is recommended
For patients with advanced fibrosis (METAVIR stage F3 or F4), screening for HCC via ultrasound every 6 months is recommended
Evaluation for retreatment is recommended as alternative treatments become available
Transition
This table outlines the recommended follow-up for patients who do not achieve an SVR following antiviral treatment.
Key Points
SVR typically halts the progression of liver disease and results in regression of liver fibrosis in most patients
Although the risk is lower than in persistently viremic individuals, patients with advanced liver fibrosis continue to be at risk for development of hepatocellular carcinoma after achieving an SVR
Similarly, patients with cirrhosis who achieve an SVR may still be at some risk for HCC and should be subject to regular surveillance for HCC
They should also receive routine surveillance endoscopy to detect esophageal varices
Periodic testing for HCV reinfection is recommended for patients who have ongoing risk for HCV infection. It is important to note that antibody to HCV remains positive following SVR in most patients, so testing for reinfection should be done with a quantitative HCV RNA assay rather than an anti-HCV serology test
Reference
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.

35. Post-treatment Monitoring Following SVR
Recommended follow-up for patients who achieve an SVR
For patients without advanced fibrosis (METAVIR stage F0-F2), recommended follow-up is the same as if they were never infected with HCV
For patients with advanced fibrosis (METAVIR stage F3 or F4), surveillance for HCC with twice-yearly ultrasound is recommended
If cirrhosis is present, a baseline endoscopy is recommended to screen for varices
Among patients with ongoing risk for HCV infection or in whom otherwise unexplained hepatic dysfunction develops, assessment for HCV recurrence or reinfection is recommended
Because antibody to HCV remains positive in most patients following an SVR, testing for reinfection should be performed with a quantitative HCV RNA assay rather than an anti-HCV serology test
If patients develop persistently elevated abnormal liver function tests after achieving an SVR, assess for other causes of liver disease
Transition
This table outlines the recommended follow-up for patients who do achieve an SVR following antiviral treatment.
Key Points
SVR typically halts the progression of liver disease and results in regression of liver fibrosis in most patients. Therefore patients who do not have evidence of advanced fibrosis should receive standard medical care as recommended for patients who were never infected with HCV
Although the risk is lower than in persistently viremic individuals, patients with advanced liver fibrosis continue to be at risk for development of HCC after achieving an SVR
Similarly, patients with cirrhosis who achieve and SVR may still be at some risk for HCC and should be subject to regular surveillance for HCC
They should also receive routine surveillance endoscopy to detect esophageal varices
Periodic testing for HCV reinfection is recommended for patients who have ongoing risk for HCV infection. It is important to note that antibody to HCV remains positive following SVR in most patients, so testing for reinfection should be done with a quantitative HCV RNA assay rather than an anti-HCV serology test
Reference
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.
AASLD/IDSA. Recommendations for testing, managing, and treating hepatitis C. Accessed March 3, 2016.

36. Summary
At least 3.5 million people in the United States are chronically infected with HCV
It is estimated that only half of those infected are diagnosed
Recommendations for managing patients with CHC include:
Baseline screening for all patients initiating antiviral treatment, including fibrosis assessment and assessment for comorbidities and other factors that may affect treatment response
Monitoring while on treatment to assess virologic and other laboratory/clinical effects of treatment
Post-treatment monitoring according to whether patients achieve an SVR (virologic cure) or not
The approval of DAAs for the treatment of HCV has resulted in substantial improvements in the overall rates of SVR (virologic cure)
Long-term, achieving an SVR may be associated with numerous clinical, economic, and quality-of-life benefits
Transition
Here is a summary of the key points discussed in the presentation.
Key Points
At least 3.5 million people in the United States are chronically infected with HCV
It is estimated that only half are diagnosed
Recommendations for managing patients with CHC include:
Baseline screening for all patients initiating antiviral treatment, including fibrosis assessment and assessment for comorbidities and other factors that may affect treatment response
Monitoring while on treatment to assess virologic and other laboratory/clinical effects of treatment
Post-treatment monitoring according to whether patients achieve an SVR (virologic cure) or not
The approval of DAAs for the treatment of HCV has resulted in substantial improvements in the overall rates of SVR/cure
Long-term, achieving an SVR may be associated with numerous clinical, economic, and quality-of-life benefits

37. Thank you!
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