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Advances in Hepatitis C
Identification and Treatment
Camilla S. Graham, MD, MPH
Division of Infectious Diseases
Beth Israel Deaconess Medical Center
Hepatitis C and Occupational Health
• Hepatitis C affects 4 -5 million people in the
US. Impact on employees:
– Risk of infection through percutaneous exposure
during work procedures
– May be previously infected and could develop
severe complications if not identified
– May need to take time to care for affected family
members
Occupational Risk of HCV Exposure
• Risk of HCV infection after needle stick (3% ?)
between hepatitis B (up to 30%) and HIV
(0.3%)
• Very unlikely with blood to mucosal contact or
contact with body fluids other than blood
• Integrate HCV management into broader
infectious exposure protocol
– Note that CDC recommendations for occupational
health exposure need to be updated (2001)
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5011a1.htm
Brief Overview of Infectious Disease
Management
• Decide if exposure could transmit HIV (if so, would assume
potential HCV and HBV transmission)
– Truvada+raltegravir x 28 days (first line)
– CBC, Cr, LFTs
– HIV Ab weeks 6, 12 and 24
• Check anti-HBs:
– Negative: Vaccinate (or give HBIG if possible non-converter;
consider chronic HBV infection)
– Positive: Protected
• Check HCV antibody
–
–
–
–
Positive: check HCV RNA, refer for further management
Negative: Recheck HCV Ab and ALT at weeks 6, 12 and 24
If HCV Ab+, symptoms or ALT increase, check HCV RNA
Counsel on transmission risks (condoms, do not share personal
items like razors or clippers)
75% of People with Hepatitis C
in the US are Baby Boomers
Identifying Patients with Hepatitis C
•
4-5 million people in the US have hepatitis C virus (HCV)
infection
– NHANES estimates 3.2 million infected but this national survey excludes
people who do not have a permanent address (homeless, incarcerated,
nursing home residents), active military, and under-represents most
groups outside White, African-American, and Mexican-Hispanic
– Accounting for under-represented international populations, homeless,
and groups that have a high prevalence like IDU and veterans gives the
5+ million estimate
•
Most were infected in 1960’s through 1980’s
– Up to 250,000 cases per year in 1980’s
– About 50% infected via IDU, rest from blood transfusions, sex,
tattoos, medical procedures, and other factors
Smith BD et al. MMWR. August 17, 2012/61(RR04);1-18. Armstrong GL et al. Ann Intern Med. 2006 May 16;144(10):705-14.
6
http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-andC.aspx; Rein et al. Dig Liver Dis 2011; 43:66
Identifying Patients with Hepatitis C
•
Up to 75% of people have not been diagnosed
– 50% to 75% is estimated
•
Risk-based screening misses many people
– Overburdened primary care
– Lack of knowledge for patients and providers
– Stigma associated with IDU, even if decades ago
•
Leading cause for liver transplantation and liver cancer (HCC)
− 37% lifetime risk of HCV-related mortality for patients with chronic
HCV
Smith BD et al. MMWR. August 17, 2012/61(RR04);1-18. Armstrong GL et al. Ann Intern Med. 2006 May 16;144(10):705-14.
7
http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-andC.aspx; Rein et al. Dig Liver Dis 2011; 43:66
Number People with Reactive anti-HCV Antibody
Estimates of People with Hepatitis C in
Massachusetts
Population age ≥18 in Massachusetts is 5,128,706
200000
180000
160000
140000
120000
100000
80000
60000
40000
20000
0
Hepatitis C
NHANES
Adjust for Excluded Massachusetts DPH
Groups
United States Census Bureau 2010: Age and Sex Compositions (http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf; accessed
7/23/14); Ditah et al. J Hepatology 2014; 60:691 - NHANES HCV survey found 1.3% prevalence anti-HCV in US population age >18; Chak et
al. Liver International 2011; 31:1090 - Adjustment for groups excluded from NHANES including homeless, incarcerated, active military and
nursing home residents
Efficient Identification of Patients with HCV
50 million “risk
identified” or ~80
million 19451965 cohort who
need to be
tested for HCV in
US1
4 -5 million
people with
HCV in US
25%
diagnosed
with HCV
Treatment and
Management
Improve
Diagnosis
1Tomaszewski
Am J Public Health 2012; 102 (11):e1019
Number with chronic HCV (millions)
Baby Boomers (Born in 1945–1965)
Account for 76.5% of HCV in the US1
1.6
Estimated Prevalence by Age Group2
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
<192
0
1920s
1930s
1940s
1950s
1960s
1970s
1980s
1990+
Birth Year Group
An estimated 35% of undiagnosed baby boomers with HCV currently have advanced fibrosis
(F3-F4; bridging fibrosis to cirrhosis)3
10
1. Centers for Disease Control and Prevention. MMWR. 2012;61:1-32; Adapted from Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a baby boomer
Epidemic of Liver Disease. New York, NY: Milliman, Inc; May 18, 2009. http://www.milliman.com/expertise/healthcare/publications/rr/consequences-hepatitis-c-virus-RR0515-09.php Milliman report was commissioned by Vertex Pharmaceuticals; 3. McGarry LJ et al. Hepatology. 2012;55(5):1344-1355.
Who Should Be Tested for HCV
CDC Recommendations
USPSTF Grade B Recs*
•
•
Everyone born from 1945 through
1965 (one-time)
•
Past or present injection drug use
•
Sex with an IDU; other high-risk sex
•
Blood transfusion prior to 1992
•
Persons with hemophilia
•
Long-term hemodialysis
•
Born to an HCV-infected mother
•
Incarceration
•
Intranasal drug use
•
Receiving an unregulated tattoo
•
Occupational percutaneous
exposure
•
Surgery before implementation of
universal precautions
•
•
•
•
•
•
•
•
Everyone born from 1945 through
1965 (one-time)
Persons who ever injected illegal
drugs
Persons who received clotting factor
concentrates produced before 1987
Chronic (long-term) hemodialysis
Persons with persistently abnormal
ALT levels.
Recipients of transfusions or organ
transplants prior to 1992
Persons with recognized
occupational exposures
Children born to HCV-positive
women
HIV positive persons
11 testing
*Only pertains to persons with normal liver enzymes; if elevated liver enzymes need HBV and HCV
Smith at al. Ann Intern Med 2012; 157:817-822. Moyer et al. Ann Intern Med epub 25 June 2013
Massachusetts Hepatitis C Testing
Law: Section 138; Chapter 111
•
Every person born between the years of 1945
and 1965 who receives health care services
from a primary care provider shall be offered a
hepatitis C screening test or a hepatitis C
diagnostic test unless the provider believes that:
(i) the person is being treated for a life
threatening emergency; (ii) the person has
previously been offered or has received a
hepatitis screening test; or (iii) the person lacks
capacity to consent to a hepatitis C screening
test.
12
http://www.mass.gov/bb/gaa/fy2015/prnt_15/os_15/p138.htm
Ms. Smith
• 55 y/o woman followed for 12 years in
primary care for anxiety and recently for
menopause. Three years ago noted to have
ALT 60 after estrogen replacement so
switched to transdermal gel and follow up
ALT 40.
• Presented with URI and found to have Hgb
9.3 and platelets 81,000. Additional testing
showed ALT 36, AST 82, Albumin 2.7, total
bilirubin 1.0 and INR 1.2.
13
Ms. Smith
•
•
•
HCV antibody positive
HCV RNA 16,500
Genotype 1a
14
Ms. Smith
•
•
•
CT abdomen with nodular liver, spleen 13.8 cm
and small amount of ascites
EGD with two grade 1 esophageal varices
Hepatic encephalopathy?
15
Ms. Smith
•
Only possible “risk exposure” was foot surgery
at a free-standing podiatry clinic in 1982
16
Chronic HCV Infection May Lead to
Chronic Liver Disease and Liver Cancer
Fibrosis
Cirrhosis
Hepatocellular Carcinoma
(with cirrhosis)
HCC3
Cancer of the liver
can develop after
years of chronic
HCV infection
Fibrosis1
Chronic HCV
infection can
lead to the
development of
fibrous scar
tissue within
the liver
Decompensated
cirrhosis:
Cirrhosis1,2
Over time, fibrosis can
progress, causing severe
scarring of the liver,
restricted blood flow,
impaired liver function,
and eventually liver failure
Ascites
Bleeding gastroesophageal
varices
Hepatic encephalopathy
Jaundice
Chronic liver disease includes fibrosis, cirrhosis, and hepatic decompensation; HCC=hepatocellular carcinoma.
1. Highleyman L. Hepatitis C Support Project. http://www.hcvadvocate.org/hepatitis/factsheets_pdf/Fibrosis.pdf. Accessed August 18, 2011; 2. Bataller
17
R et al. J Clin Invest. 2005;115:209-218;
3. Medline Plus. http://www.nlm.nih.gov/medlineplus/enxy.article/000280.htm. Accessed August 28, 2012; 4. Centers for Disease Control and
Prevention. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed May 8, 2012.
Deaths Due to HCV Infections Now Exceed
Those Due to HIV Infection
Hepatitis C
Rate per 100,000 Persons
7
HIV
16,600 deaths
6
5
4
3
2
1
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Year
Number of HCV-related deaths may
be over 60,000 because of underreporting on death certificates
Ly KN, Xing J, Klevens RM, Jiles RB, Holmberg SD. Causes of death and characteristics of decedents with viral hepatitis, United States, 2010.
Clin Infect Dis. 2014 Jan;58(1):40-9. Mahajan, IDSA 2013
Projected Numbers of Decompensated Cirrhosis and
Cases of HCC to Rise Through 2020
Timing of Mortality Among Known HCV
Cases in Massachusetts, 1992-2009
1800
Median interval: 3 years
Median age: 53 years
Number of deaths
1600
1400
1200
1000
800
600
400
200
0
<1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Years to death from date of HCV diagnosis
N=8,499
76,122 HCV diagnoses were reported to the MDPH between 1992 and 2009, 8,499 of
these reported HCV cases died and are represented in the figure. Data as of 1/11/2011.
20
Lijewski, et al, 2012
15
16
17
Screening of Baby Boomers May Prevent >120,000
Deaths Due to HCV Infection
1,070,840 new cases of HCV
identified with birth-cohort
screening
552,000 patients treated
364,000 patients
cured*
121,000 deaths
averted†
› Birth-cohort screening in primary care would identify 86% of all undiagnosed cases in
the birth cohort, compared with 21% under risk based screening1
› Cost effectiveness of HCV screening is comparable to cervical cancer or cholesterol
screening (cost/QALY gained with protease inhibitor+IFN+RBV = $35,700)
Markov chain Monte Carol simulation model of prevalence of hepatitis C antibody stratified by age, sex, race/ethnicity, history of injection drug use, and natural history of chronic hepatitis C.
*With pegylated interferon and ribavirin plus DAA treatment.
†Deaths due to decompensated cirrhosis or hepatocellular carcinoma within 1945-1965 birth cohort. 470,000 deaths under birth cohort screening vs 592,000 deaths under risk-based screening
1. Rein D et al. Ann Intern Med. 2012;156(4):263-270; 2. McGarry LJ et al. Hepatology. 2012;55(5):1344-1355.
21
Efficient Identification of Hepatitis C
in a Health Care Setting
22
BIDMC/CareGroup Experience
• Network of academic hospitals, primary care
practices, community health centers that share a
common electronic medical record system
– 5,500 clinicians and ~1.5 million patients
• Implemented a prompt in EMR for a one-time
anti-HCV test in all patients born from 1945-1965
who had no prior record of testing, while
continuing risk-based testing
– Went live on June 4, 2013
– In the first ten months, we tested a total of 20,000
people for HCV
Steps to Implement Birth Cohort HCV Testing
• Build a core team: Primary Care, Infectious Disease, Hepatology,
Database Management, and Clinical Pathology
• Implement a one-time electronic prompt for anti-HCV antibody testing
for all patients born from 1945 through 1965 who have no record of
HCV antibody testing
• One-page educational tool for providers and one for patients (samples
at KNOW MORE HEPATITIS/CDC and NVHR.org)
• Email notification to affected clinicians
• HCV nurse educator
– Help facilitate patient referral in the Liver Center and Infectious Diseases
Clinic
• Slide deck for presentations to primary care providers about HCV
(sample at NVHR.org)
• Collaboration with Laboratory Services
– Expand capacity for increased volume of HCV Ab and RNA tests
– Add language to results page (or a second prompt) for all positive HCV
antibody tests informing clinicians to order an HCV RNA test to determine
the presence of active HCV infection
– Generates a report of all positive HCV antibody tests for follow up
Address Primary Care Provider Concerns
• Address misconceptions about hepatitis C:
– Hepatitis C causes substantial morbidity and mortality
– Patients can have normal labs and exam and have cirrhosis
– It is nearly impossible to implement comprehensive risk-based
screening in general population primary care
– Hepatitis C is curable and most patients will not require IFN
– Many patients will not require a liver biopsy
• Expect that PCPs will test all patients with reactive anti-HCV
Ab tests for HCV RNA
• Engage PCPs for alcohol screening and counseling,
vaccinations, transmission risk reduction, referral for
addiction treatment and harm reduction counseling
• Remind PCPs about value of identifying cirrhotic patients
before they develop complications
• Provide support (education/nursing support, emails,
telemedicine)
25
Initial Hepatitis C Testing and Evaluation
Who Should Be Tested for Hepatitis C?
New: Anyone born between 1945 and 1965
should be tested once, regardless of risk
factors
In addition, patients with the following risk factors:
• Elevated ALT (even intermittently)
• A history of illicit injection drug use or intranasal
cocaine use (even once)
• Needle stick or mucosal exposure to blood
• Current sexual partners of HCV infected persons
• Received blood/organs before 1992
• Received clotting factors made before 1987
• Chronic hemodialysis
• Infection with HIV
• Children born to HCV-infected mothers
Why Test People Born Between 19451965?
• 76% of the ~4 million people with HCV infection
in the US are baby boomers
• In the 1945-1965 cohort:
• All: 1 out of 30
• Men: 1 out of 23
• African American men: 1 out of 12
• Up to 75% do not know they have HCV
• 73% of HCV-related deaths are in baby boomers
What Can Happen to People with
Hepatitis C?
• It is important to identify if patients have cirrhosis
• Patients with cirrhosis are at risk for liver cancer
(HCC) and liver decompensation (ascites, variceal
bleed, hepatic encephalopathy, jaundice)
• Hepatitis C is curable, and cure reduces the risk of
severe complications, even with cirrhosis
• Refer patients to a specialist who has experience
treating hepatitis C to see if they need treatment
Hepatitis C Antibody
(HCV Ab)1
Negative (-)
STOP here if no concern for acute
infection or severe immunosuppression.
If so, check HCV RNA.
Positive (+)
These people are NOT chronically infected.
Check HCV RNA
(viral load)
Negative (-)
•
Positive (+)
Detectable HCV Ab with negative HCV RNA
can occur with spontaneous clearance of
infection ( about 25% of people exposed to
HCV will clear; verify HCV RNA negative in 4
to 6 months) or with treatment of HCV.
Hepatitis C infection
1Example
Evaluation and referral
ICD-9 codes for HCV antibody testing:
• V73.89: screening for other specified viral disease
• 790.4: nonspecific elevation of levels of
transaminase; use if patient ever had an elevated ALT
Counsel Patients with HCV Infection About Reducing Risk of
Transmission
• Do not donate blood, body organs, other tissue, or semen
• Do not share personal items that might have small amounts of blood (toothbrushes, razors,
nail-grooming equipment, needles) and cover cuts and wounds
• HCV is not spread by hugging, kissing, food or water, sharing utensils, or casual contact
• If in short term or multiple relationships, use latex condoms. No condom use is
recommended for long-term monogamous couples (risk of transmission is very low)
Initial Management
• Evaluate alcohol use (CAGE, AUDIT-C) and recommend stopping use
• Vaccinate for hepatitis A and hepatitis B if not previously exposed
• Evaluate sources of support (social, emotional, financial) needed for HCV treatment
26
Smith BD et al. MMWR. August 17, 2012/61(RR04); 1-18. Adapted from Winston et al. Management of hepatitis C by the
primary care
provider: Monitoring guidelines; 2010; http://www.hcvadvocate.org/hepatitis/factsheets_pdf/PCP_web_10.pdf
PCP Education Example: Screening
in Clinic
1,000
adult
patients
Efficiently identify
birth cohort 19451965:
• Electronic
prompt
330
baby
boomers
~1/3 of
adults are
in 19451965
cohort
10
HCV
antibody
positive
•
•
•
1 of 30 baby
boomers
1 of 23 men
baby boomers
1 of 12 African
American men
baby boomers
7 HCV
RNA
positive
3 with more
advanced
fibrosis
4 with mild
fibrosis
15%-30% of
HCV antibody
patients will
spontaneously
clear
Up to 25% of
baby boomers
may have
cirrhosis
75% of cirrhotic
patients are
men
27
Davis, Gastro 2010; 138: 513
Number of HCV Antibody Tests Performed
In Four Week Intervals
2500
2000
1500
Total Tests
1000
Boomers
Non-Boomers
500
3/1/2014
1/1/2014
11/1/2013
9/1/2013
7/1/2013
5/1/2013
3/1/2013
1/1/2013
11/1/2012
9/1/2012
7/1/2012
5/1/2012
3/1/2012
1/1/2012
0
Beth Israel Deaconess Medical Center, Boston, MA, Quality Outcomes Data, 1/22/14
HCV Antibody Test Volume Increased after
EMR Prompt
Boomers
Average = 1192
tests/4 weeks
1600
EMR
prompt
1400
1200
CDC 19451965 testing
guidelines
1000
800
600
Average = 303
tests/4 weeks
Average = 438
tests/4 weeks
Boomers
400
200
3/1/2014
1/1/2014
11/1/2013
9/1/2013
7/1/2013
5/1/2013
3/1/2013
1/1/2013
11/1/2012
9/1/2012
7/1/2012
5/1/2012
3/1/2012
1/1/2012
0
Beth Israel Deaconess Medical Center, Boston, MA, Quality Outcomes Data, 6/5/14
More Women Tested for HCV but
More Men are Anti-HCV Positive
Group
Number (%) Tested for
HCV Ab
Anti-HCV Seroprevalence (%)
13,107
2.3%
Boomer women
7,555 (58%)
1.4% (34% of HCV Ab+ results)
Boomer men
5,552 (42%)
3.6% (66% of HCV Ab+ results)
7,022
2.6%
Non-Boomer women
4,023 (57%)
1.9% (42% of HCV Ab+ results)
Non-Boomer men
2,999 (43%)
3.5% (58% of HCV Ab+ results)
All Boomers
All Non-Boomer
Beth Israel Deaconess Medical Center, Boston, MA, Quality Outcomes Data, 6/5/14
Initial Approach to Patients
Diagnosed with Hepatitis C
Hepatitis C Diagnosis has been Made:
What to Discuss with the Patient
•
Do not donate blood. May donate organs to others with HCV
•
Do not share personal items that might have small amounts of blood
–
Toothbrushes, razors, nail-grooming equipment
•
HCV is not spread by hugging, kissing, food or water, sharing utensils,
or casual contact
•
If using illicit drugs, stop using. If continued, get into a treatment
program and do not share needles, syringes or works
–
•
Concern among payers about poor adherence and reinfection after antiviral Rx
If in short term, multiple or MSM relationships, use latex condoms. No
condom use is recommended for long-term monogamous
heterosexual couples
–
Maximum incidence rate of HCV sexual transmission estimated about 1 new infection
per 190,000 sexual contacts per year (Terrault, Hepatology. 2013; 57(3):881)
•
Limit Tylenol to 2 gm a day and discuss all other medications
(including OTC and herbal ) with a provider
•
Check exposure status for hepatitis A and B and vaccinate if needed
Adapted from Winston et al. Management of hepatitis C by the primary care provider: Monitoring guidelines; 2010
http://www.hcvadvocate.org/hepatitis/factsheets_pdf/PCP_web_10.pdf
Address Alcohol Use in HCV
•
•
•
•
The CDC recommends brief alcohol intervention for
all patients with HCV
There is no “safe” amount of alcohol consumption
Insist on absolute abstinence if patient has bridging
fibrosis or cirrhosis
Assess for risky alcohol use
– Men: >2 drinks/day (>14/week) or more that 4 in one day
– Women: >1 drink/day (>7/week) or more than 3 in one day
•
Screen for alcohol misuse
– How many times in the past year have you had X or more
drinks in a day?”, where X is 5 for men and 4 for women, and
a response of >1 is considered positive
http://www.integration.samhsa.gov/images/res/tool_auditc.pdf
33
Moyer et al. Screening and Behavioral Counseling Interventions in Primary Care to Reduce Alcohol Misuse: USPSTF
Recommendation Statement. Annals Int Med; 14 May 2013 online
Baseline Labs in Patients with Newly
Diagnosed HCV
•
HCV RNA “viral load” (determines active infection)
•
Hepatitis C genotype (determines treatment choice)
•
Complete blood count (platelets <150,000 assc with cirrhosis)
•
INR, Albumin, Total bilirubin (abnormal liver synthetic function
often indicates advanced liver disease)
•
Creatinine, Glucose, ALT, AST, Alkaline Phosphatase
•
Hepatitis A serology: total or IgG (vaccinate if nonreactive)
•
Hepatitis B serology: HBsAb, HBcAb, HBsAg (vaccinate if all
nonreactive)
•
HIV antibody
•
Iron studies, ANA
•
Assessment of liver fibrosis (such as Hepascore, Fibrotest,
APRI, FIB-4, Fibroscan)
34
BIDMC HCV ECHO Program Recommendations, 2014
Distribution of Fibrosis Scores
•
•
•
•
•
F0 = 15%
F1 = 25%
F2 = 20%
F3 = 15%
F4 = 25%
Recently infected and slow progressors
“Advanced fibrosis
• Limits of fibrosis tests:
– Liver biopsies are +/- 1 fibrosis stage
– Noninvasive tests are best at determining a high
versus low probability of advanced fibrosis
35
Determine Likelihood of Cirrhosis
• Noninvasive test results increase the likelihood of
cirrhosis, especially if more than one are present:
– APRI >1.5 or FIB-4 >3.25 (use on-line calculators)
• FIB-4 more predictive of ESLD than liver biopsy (CROI 2014)
–
–
–
–
Hepascore or Fibrotest >0.74
Fibroscan >12.5
Platelets <150,000
Albumin < 3.5
• Splenomegaly on exam or ultrasound
• Any signs of liver decompensation
• MELD and Child-Pugh scores (use on-line calculators)
Chou, Annals Int Med 2013; 158:807; Bonder, Curr Gastro Rep 2014; 16:372;
Berenguer #640 and Lo Re #650 CROI 2014
FibroScan - Transient Elastography
• Ultrasound determines
velocity of shear wave
in m/s, which is
proportional to liver
stiffness in kilopascal
(kPa)
• Entire process requires
15 to 20 minutes,
provides immediate
results
• Falsely elevated results:
– High ALT (>100)
– Eating within 2 hours
Bonder, Curr Gastro Rep 2014; 16:372
ALV 10.7.13
Continuum of Fibrosis/Cirrhosis in HCV
<7 kPa = Stage 0-1
7-9.5 kPa = Stage 2
9.5-12.5 kPa = Stage 3
>12.5 kPa = Cirrhosis
>20 kPa = Increased risk
liver-related complications
Continuum of scores (in kPa)
Bonder, Curr Gastro Rep 2014; 16:372
70+ kPa
Management of Patients with Hepatitis
C and Cirrhosis
39
• Every 6 month screening for liver cancer
• Usually ultrasound
• Consider CT or MRI if highly nodular liver; first exam
• Screening for esophageal varices
• Repeat every 1 -3 years depending on results
• Counsel on symptoms of hepatic encephalopathy
• Vaccination for pneumococcus
• Counseling around medication use to avoid overdose or
adverse events (including common drugs like Tylenol and
NSAIDS)
• Counseling about complete abstinence from alcohol
• Evaluation for antiviral treatment
• Cure of HCV can reduce liver failure and liver cancer, even in
patients with cirrhosis (+/- HIV coinfection)
• Possible referral for liver transplant services
http://www.aasld.org/practiceguidelines/pages/guidelinelisting.aspx
10-year Cumulative Incidence Rate
SVR (Cure) Associated with
Decreased All-Cause Mortality
29.9
26
21.8
8.9
Van der Meer et al. JAMA 2012; 308:2584
5.1
2.1
530 patients with
advanced fibrosis,
treated with interferonbased therapy, and
followed for 8.4 (IQR
6.4-1.4) years
Recent Treatment Data and
Guidelines
Variables Important in HCV Management
and Treatment Decision Making
• Genotype: 1, 2, 3, 4, 5 and 6
• Stage of liver fibrosis: F0-1 (mild), F0-F2 (mild to moderate), F2-F4
(moderate to advanced), F3-F4 (advanced), F4 (cirrhosis)
• Cirrhosis severity: Compensated (Child A), cirrhosis with portal
hypertension, Decompensated (Child B/C), Clinical decompensation
• Hepatocellular carcinoma (and stage)
• Pre-Transplant
• Post-Transplant
• Extra-hepatic complications (renal, lymphoma, cryoglobulinemia, etc)
• Psychological distress from HCV infection
• Coinfections: HIV, HBV
• Prevention of transmission: Women pre-pregnancy, MSM, active IDU
Variables Important in HCV Management
and Treatment Decision Making
• Naïve
• Previous treatment:
– P/R relapse, P/R partial responder, P/R null
responder
– Telaprevir/boceprevir failure (? Importance of
relapse vs. nonresponder/breakthrough)
– Sofosbuvir/RBV +/- IFN failure
– Sofosbuvir/simeprevir failure
– Other clinical trial failures
Multiple Validated Drug Targets
HOST
Core E1
E2
p7
5’UTR
Helicase
None
None
NS2
Protease
HCV PIs
NS3
4A
MIR 122 Inhibitors
- MIravirsen
HOST
NS5A
Inhibitors
Viral enzyme
Active site
Non-enzyme
Replication complex
Telaprevir
Boceprevir
Simeprevir
Faldaprevir
Asunaprevir
Daneoprevir
Paritaprevir
MK-5172
Sovaprevir
ACH-2684
Daclatasvir
Ledipasvir
Ombitasvir
GS-5816
ACH-3102
PPI-668
GSK2336805
Samatasvir
MK-8742
Cyclophilin
Inhibitors
- Alisporivir
-SCY-635
Membraneous web (Preclin)
NS4B NS5A
3’UTR
NS5B
Polymerase
NS5B
Nucs
NS5B
Non-nucs
Viral enzyme
Active site
Viral enzyme
Allosteric site
Sofosbuvir
Meracitabine
IDX20963
ACH-3422
Dasabuvir
Deleobuvir
BMS-791325
PPI-383
GS-9669
TMC647055
Graphic courtesy of Dr John Link,
Not all-inclusive.
Slide 45 of 30
The World is Rapidly Changing in HCV
•
•
•
•
•
•
•
•
•
•
Pegylated interferon (Peg-IFN) + ribavirin (RBV)
Peg-IFN + RBV + Telaprevir
Peg-IFN + RBV + Boceprevir
Peg-IFN + RBV + Simeprevir
Sofosbuvir+Ledipasvir x 8 weeks
Paritaprevir/r/ombitasvir+dasabuvir+/-RBV x 12 weeks
Sofosbuvir +RBV x 12 weeks
Sofosbuvir+Ledipasvir x 12 weeks
Sofosbuvir+Simeprevir x 12 weeks
Paritaprevir/r/ombitasvir+dasabuvir+/-RBV x 24 weeks (geno 1a
cirrhotic [F3-F4] null [non-] responders?)
• Sofosbuvir+RBV x 24 weeks
• Sofosbuvir+Ledipasvir x 24 weeks
• Sofosbuvir+RBV x 48 weeks
Slide 46 of 30
Percent SVR
SVR in Genotype 1, Naïve, Non-cirrhotic Patients
Treated with Sofosbuvir+Ledipasvir (ION-3)
100
90
80
70
60
50
40
30
20
10
0
97%
90%
96%
96%
119/
123
83/
92
126/
131
82/
85
8 wks VL <6 mil 8 wks VL > 6 mil 12 wks VL <6
mil
Harvoni package insert, 10/11/14
12 wks VL >6
mil
46
Slide 47 of 30
Key Points with Sofosbuvir+Ledipasvir
• Most common AEs are fatigue and headache
• Taken with or without food
• Ledipasvir needs acid for solubility/absorption
– Be careful with OTC acid blockers (TUMS, Rolaids, Mylanta,
calcium supplements, as well as proton pump and H2)
• eGFR >30 mL/min/1.73m2
• No dose adjustment for Child-Pugh Class A, B, or C
cirrhosis
• Pregnancy Class B
• Avoid P-gp inducers; see all other DDI data in PI
47
Harvoni package insert, 10/11/14
Slide 48 of 30
Percent SVR
SVR in Genotype 1, Treatment-Experienced Patients
Treated with Sofosbuvir+Ledipasvir (ION-2)
100
90
80
70
60
50
40
30
20
10
0
95%
86%
99%
100%
83/
87
19/
22
85/
86
22/
22
12 wks no
cirrhosis
12 wks cirrhosis
24 wks no
cirrhosis
24 wks cirrhosis
Harvoni+Ribavirin for 12 weeks has similar SVR rates
as Harvoni for 24 weeks
48
Harvoni package insert, 10/11/14
Slide 49 of 30
SVR-12 in Genotype 1 Patients Treated with
Paritaprevir/r+Ombitasvir+Dasabuvir +/- RBV (3-D)
Naïve, no cirrhosis,
Geno 1b:
Viekira Pak x12 wks
Percent SVR
Naïve, no cirrhosis,
Geno 1a:
Viekira Pak+RBV x12
wks
Naïve, cirrhosis, Geno
1a or 1b:
Viekira Pak+RBV x12
wks
Peg-IFN/RBV failure,
Geno 1b:
Viekira Pak+RBV x12
wks
N=473
N=297
N=209
N=91
N=100
N=208*
Feld; NEJM 2014 Apr 11; Zeuzem; NEJM 2014 Apr 10; Poordad NEJM 2014 Apr 12
Peg-IFN/RBV failure ,
Geno 1a:
Viekira Pak+RBV x 24
wks (may use 12 wks if
relapse, or no
cirrhosis)
Slide 50 of 30
Everson AASLD 2014
Colombo AASLD 2014
Slide 52 of 30
Compare Key Attributes of Harvoni vs.
Viekira Pak
Harvoni
Viekira Pak
SVR ≥95% with correct duration
SVR ≥92% with correct duration (may
have better efficacy in geno 1b)
Very well tolerated
Needs monitoring for anemia, dose
reduce RBV (<10%)
Pts with decompensation and post-Tx
need RBV
85% of patients need RBV
One pill once a day
10 pills a day (if require generic RBV)
8 to 12 week duration
12 to 24 week duration
Can use with Child B and C
Cannot use with Child B and C
Common DDIs: HIV meds, acid blockers
Common DDIs: HIV meds, Estradiol,
fluticasone, salmeterol, some statins
Fail with NS5A resistance
Fail with 3-drug class resistance
52
Genotype 2
Naïve, with or
without cirrhosis
or
Treatment
experienced, no
cirrhosis
Sofosbuvir+RBV
x 12 weeks
Treatment
experienced,
with cirrhosis
Sofosbuvir+RBV
x 12-16 weeks
2014 IDSA/AASLD Recommendations: www.hcvguidelines.org
Sofosbuvir+PegIFN+RBV x 12
weeks
Percent SVR
SVR in Genotype 2 Patients Treated with
Sofosbuvir+Ribavirin for 12 Weeks
Treatment
experienced, cirrhotic
patients only had a
78% SVR with 16
weeks SOF+LDV. May
wait for sofosbuvir +
daclatasvir
EASL 2014
Genotype 3
Naïve, with or
without cirrhosis
or
Treatment
experienced, no
cirrhosis
Sofosbuvir+RBV x
24 weeks
Sofosbuvir+PegIFN+RBV x 12 weeks
www.hcvguidelines.org
Treatment
experienced, with
cirrhosis
Sofosbuvir+PegIFN+RBV x 12
weeks
Sofosbuvir+Ledipasvir
+ RBV x 12 weeks?
Sofosbuvir+Daclatasvir
(Compassionate use until
Sofosbuvir+RBV x
24 weeks
FDA approval)
Percent SVR
SVR in Genotype 3 Patients Treated with
Sofosbuvir+Ledipasvir +/- Ribavirin for 12 Weeks
100
90
80
70
60
50
40
30
20
10
0
16/
25
26/
26
25/
28
16/
22
SOF+LDV
SOF+LDV+RBV SOF+LDV+RBV SOF+LDV+RBV
No Cirrhosis
No Cirrhosis
Cirrhosis
Treatment Naive
Gane, EASL 2014 and Gane, AASLD 2014
Treatment Experienced
Genotype 4: Sofosbuvir + Ledipasvir x 12 Weeks
• Subjects from
US, Egypt,
Ethiopia,
Cameroon
• 33% cirrhosis
• 38%
treatment
experienced
Kapoor AASLD 2014
Percent SVR
Genotype 4: Ombitasvir + Paritaprevir/r
+/- RBV x 12 Weeks
100
90
80
70
60
50
40
30
20
10
0
40/
44
Omb+Par/r
42/
42
Omb+Par/r+RBV
Treatment Naive
Pol, AASLD 2014
49/
49
Omb+Par/r+RBV
Treatment
Experienced
-Patients from
US, Europe,
Turkey
-F0-F1 = 77%
-Cirrhosis
excluded
-47% of
treatmentexperienced
patients = null
responders
Percent SVR
Sofosbuvir+Ledipasvir for 12 Weeks in Treatment
Naïve, Genotype 1, Non-cirrhotic Patients with
HIV/HCV Coinfection
100
90
80
70
60
50
40
30
20
10
0
13/
13
36/
37
ARV Untreated
ARV Treated
Osinusi AASLD 2014
-HIV regimens:
TDF/FTC,
Efavirenz,
Raltegravir,
Rilpivirine
-F3 = 26%
Percent SVR
Paritaprevir/r+Ombitasvir+Dasabuvir+RBV in
HIV/HCV genotype 1 Infection
100
90
80
70
60
50
40
30
20
10
0
29/
31
29/
32
12 Weeks
24 Weeks
-HIV regimens:
TDF/FTC,
Atazanavir,
Raltegravir
-Cirrhosis = 19%
-Peg-IFN/RBV
relapse, partial
and null
responder, 33%
12 week arm: one subject withdrew consent at week 10 (viral load UD); one subject relapsed
24 week arm: One subject had viral breakthrough, and two had re-infection after SVR
Wyles AASLD 2014
Slide 61 of 30
Hill, AASLD 2014
Slide 62 of 30
Jensen AASLD 2014
Slide 63 of 30
Hypothetical Costs of Not Optimizing
SVR Rates in Clinical Practice
95%
SVR in
clinical trials
85%
SVR in real
world
10% difference in SVR
rates for a $100,000
regimen result in:
•$12,384 “loss $ per
unachieved cure” for
each patient
•Cost of retreating all
patients who did not
achieve SVR
•Costs of liver
complications
(decompensation, liver
cancer, etc.) in those
who are not cured and
progress
Slide 64 of 30
HCV Treatment Initiation: BIDMC Example
• Assess patients for readiness, insurance status, and fill out clinical
assessment form
• Deliver the 1st fill of medication to provider office only
• Require teaching visit with clinical staff prior to starting treatment
• Document true start date and inform Specialty Pharmacy
• Set up ALL follow-up and lab appointments right after teaching visit
• Provide teaching handout and list of appointments to patient
• Utilize pill box / blister pack / smart phone reminder apps to enhance
medication compliance
• Specialty pharmacy with weekly or biweekly phone call to patients for
follow up assessment
• Adopt a real time tracking system (ie, TrioHealth)
– Record patient baseline characteristics and treatment regimen
– Prompt for wk 4, wk 12 viral load and SVR12 due dates
– Method of communication for provider office and specialty pharmacy
Pricing and Reimbursement
Current Negative Environment Created By High
Price of HCV Drugs
•
•
•
•
•
•
•
•
•
•
•
•
•
Confusion and doubt among HCV treaters
Fear from PCPs about testing and treatment
Fear/outrage among payers (public and private)
Hesitation in DPH/public outreach programs
Questions about integrity of CDC work (research and KNOW MORE HEPATITIS
campaign)
Declarations by prisons, state Medicaids that HCV treatment is not of value
Difficulty establishing broad baby boomer testing programs
Rationing of treatment, ie F3-F4; substance use
Conflict between provider, patient and payer over rationing
No discussion of cure-as-prevention
Justification for overt discriminatory practices like mandating clean urine
samples
Confirmation by patients that they are not “worth” treatment
Loss of vision about transformative, curative developments
HOW DID WE GET INTO THIS MESS?
Unique Aspects of Hepatitis C
• Relatively common disease
• Majority of people infected 20 – 40 years ago
(75% in 1945-1965 birth cohort)
• Peak of severe liver complications expected to
occur over this next decade, so urgency to
identify and treat people soon
• Everyone who has >1 year life expectancy is
theoretically a treatment candidate
• Pricing more similar to treatments for rare
diseases
“Standard of Care” Regimens for Hepatitis C Have Been
Expensive for Years: Examples for Treatment of Genotype 1,
Naïve, Non-Cirrhotic Patients
Regimen
Pegasys + Ribavirin x 48
weeks1
Telaprevir + PegIFN +
Ribavirin x 24 weeks2
Sofosbuvir + PegIFN +
Ribavirin x 12 weeks
Sofosbuvir+Ledipasvir x
8 weeks
Sofosbuvir + Ledipasvir x
12 weeks
SVR rates
WAC Price
Cost per SVR
41%
$41,758
$101,849
75%
$86,843
$115,791
90%
$94,421
$104,912
94%
$63,000
99%
$94,500
$67,021
($36,191?)*
$95,454
($51,545?)*
Package inserts for products; *http://blogs.wsj.com/pharmalot/2015/02/04/what-the-shocking-gilead-discounts-on-itshepatitis-c-drugs-will-mean/
Cost-Effectiveness of HCV Treatment
Study
Key Findings
Leidner, Hepatology
2015
For 55 y/o treated with $100,000 regimen and SVR = 90%,
treating at F2 compared to waiting until F3 had CE =
$37,300/QALY
Threshold cost for treating at F0 versus waiting until F1 to yield
$50,000/QALY = $22,200
Rein, CID 2015
Harvoni and Viekira Pak compared to no treatment yields
$32,000 to $35,000/QALY
Compared to no treatment, threshold cost for treating F0 with
all-oral regimen = $47,000
Najafzadeh, Annals
Int Med 2015
Compared to no treatment in genotype 1, costs per additional
QALY gained for Harvoni = $25,291 and Peg-IRN/RBV = $24,833
If Harvoni <$66,000/treatment course, would be cost saving
Chhatwal, Annals Int Average ICER for sofosbuvir-based treatment compared to prior
Med 2015
SOC = $55,378/QALY
Range = $9,703/QALY for naïve, cirrhotic geno 1 to $410,548
for treatment experienced, geno 3 without cirrhosis
Budget Impact Model
Current Environment
Key Factor
Impact On
New Environment
New
Total Population
Incidence
Prevalence
Incidence
%Diagnosed
%Treated
Diagnosis
Treatment
New
Sick Population
Sick Population
Target Population
Current
Treatment
Total Population
Hospital and
clinic visits, tests
Resource Utilization
Everyone!
New
Target Population
New
Resource Utilization
(Hospital, prescriptions)
(Hospital, prescriptions)
Unit costs
Cost of Illness
Mauskopf et al; Principles of Good Practice for Budget Impact
Analysis: Report of the ISPOR Task Force on Good Research
Practices – Budget Impact Analysis; Value in Health 2007;
10(5): 336-347.
New
Treatment
New
Cost of Illness
Difference
Budget Impact
Payer Dilemmas
• Most payers had no idea how much they were
actually spending per treated patient (or per
cure) in the interferon era
– PI/P/R in cirrhotic patients ~ $266,000 per cure1
• Pharmacy budgets often separate from medical
budgets
– Pharmacy budgets don’t get “credit” for avoidance of
medical costs
– Annual budgets
• “Is it cost effective?” (off-sets over the long term)
• “Is it affordable?” (costs over one year)
1Sethi,
AASLD 2013
Recommended regimens for patients with HCV genotype
1a or 1b infection who have compensated cirrhosis, in
whom prior PEG-IFN and RBV treatment has failed
• Daily fixed-dose combination of ledipasvir/sofosbuvir for
24 weeks
Rating: Class I, Level A
• Daily fixed-dose combination of ledipasvir/sofosbuvir plus
weight-based RBV for 12 weeks…
Rating: Class I, Level B
• Daily fixed-dose combination of
paritaprevir/ritonavir/ombitasvir plus twice-daily dosed
dasabuvir and weight-based RBV for 24 weeks is
recommended for patients with HCV genotype 1a…
Rating: Class I, Level A
• Daily sofosbuvir plus simeprevir with or without weightbased RBV for 24 weeks…
Rating: Class IIa, Level B
Cost (with
discount)
$102,600
$52,650
92,683
$162,000
Adapted from www.hcvguidelines.org
Slide 74 of 30
Prioritization Versus Rationing
• Prioritization involves determining and balancing:
– Medical needs
•
•
•
•
Immediacy of patient suffering
Risk of increasing medical complexity of management
Future costs of complications (or not intervening)
Public health risks
– Resource constraints
• Provider capacity (eg, MA has ~150,000 patients with
hepatitis C infection and ~100 HCV providers)
• Distribution of providers
• Financial limits (payer horizon typically ~1 to 3 years)
– Most of us can accept prioritization
Slide 75 of 30
Rationing
• Limiting access to medical care
• Often non-attributable in US
– Lack of or under insurance
– Lack of access to appropriate providers
– High co-pays
• Frank denial of medication coverage by payers
– Usually when a less expensive, “equivalent”
alternative is available
• Much of EU, Canada, Australia ration medicine
based on urgency of medical needs and
anticipated clinical benefit
• Can be based on bias/discrimination
Slide 76 of 30
Treatment Priority
Per AASLD/IDSA/IAS–USA HCV Guidelines
1. Patients with highest risk for severe
complications
– Advanced fibrosis or compensated cirrhosis
– Organ transplant
– Type 2 or 3 essential mixed cryoglobulinemia
with end-organ manifestations (ie, vasculitis)
– Proteinuria, nephrotic syndrome, or
membranoproliferative glomerulonephritis
Slide 77 of 30
Treatment Priority
Per AASLD/IDSA/IAS–USA HCV Guidelines
2. Patients with high risk for complications
–
–
–
–
–
–
–
Stage 2 fibrosis
HIV coinfection
HBV coinfection
Other coexistent liver disease (ie, NASH)
Debilitating fatigue
Type 2 diabetes mellitus (insulin resistant)
Porphyria cutanea tarda
Slide 78 of 30
Treatment Priority
Per AASLD/IDSA/IAS–USA HCV Guidelines
3. Persons with high transmission risk
–
–
–
–
MSM with high-risk sexual practices
Active injection drug users
Incarcerated persons
Persons on long-term hemodialysis
Slide 79 of 30
Decisions to Limit Access to HCV
Treatment
• Medical need restrictions
• Insurance restrictions
• Prescriber restrictions
• Specialty pharmacy restrictions
• Insurance termination / switch during treatment
Slide 80 of 30
Medical Need Restriction
• Advanced fibrosis (Metavir F3-F4)
– Evidenced by liver biopsy, transient elastography,
Fibrotest, APRI or FIB-4 score, radiological imaging
consistent with cirrhosis, physical findings or
clinical evidence consistent with cirrhosis as
attested by the prescribing physician
Slide 81 of 30
Response to Restricting Treatment to F3/F4
• Cannot require liver biopsy (may be highest risk
of death in HCV care with all-oral regimens)
• Since no test can perfectly distinguish F2 from F3
or F3 from F4, limiting access to F3/F4 really
means directing treatment to cirrhotic patients
• If we wait until advanced fibrosis, need to do lifelong screening for HCC every six months even if
cured (expense, logistics, patient anxiety)
• Prioritization of F2-F4 unless other compelling
urgency may align with provider capacity
Slide 82 of 30
Restrictions Based on Current or
History of Substance Abuse
• Prescriber assessment and documentation
– 3 to 12 months sobriety/abstinence from
EtOH/drug use
– Completion or enrollment in a treatment center
– May require drug testing results
• Participate in counseling services
• Engage in care with an addiction specialist
Slide 83 of 30
Compare: Department of Veterans Affairs (VA)
Guidelines for PWID
“There are no published data supporting a
minimum length of abstinence as an inclusion
criterion for HCV antiviral treatment. Patients with
active substance- or alcohol-use disorders should
be considered for therapy on a case-by-case basis
and care should be coordinated with substanceuse treatment specialists.”
• http://www.hepatitis.va.gov/provider/guidelines/
2014hcv/special-groups.asp
Center for Health Law and Policy
Innovation of Harvard Law School
Community Network in HCV
Departments of
Public Health
Academic
Centers
Slide 84 of 30
ECHO
Community
Health Centers
Government
Policy Makers
Prisons
Private Primary
Care Centers
Media
Patient
Advocacy
Organizations
Community
Gastroenterology
Commercial
Payers
Pharmacies
Government
Payers
Pharmaceutical
Companies
Slide 85 of 30
Resources
• IDSA/AASLD/IAS–USA HCV Guidance
• Federal guidelines (VA, prison system)
• National Viral Hepatitis Roundtable
– Collects templates, sample slide presentations,
analyses of state and federal policies
– Program assistance with 1945-1965 birth cohort
testing
– www.NVHR.org
Additional Provider Resources for HCV
Testing at NVHR
1. Importance of Screening in Uncertain Treatment
Climate Fact Sheet for Providers
2. Primary Care Provider Handouts & Fact Sheets
3. Birth Cohort Prompt Implementation Support
4. Continuing Medical Education (CME) resources
5. Coding & Billing Details
6. Provider Training Modules
7. Links to Treatment Guidelines
Website: http://nvhr.org/content/welcome-nvhrhepatitis-c-baby-boomer-resources-page