Transcript Antiretroviral Therapy and the Liver

Viral Hepatitis: Prevention and
Control
Mark Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/ Hepatology
Johns Hopkins Medical Institutions
Baltimore Maryland USA
Viral Hepatitis: Prevention and
Control
The US
Perspective
HCV Prevention Policy Development

Institute of Medicine

AASLD/ Trust for America’s Health
Report

HHS Plan for Viral Hepatitis
Prevention

“Development of a vaccine that
prevents new HCV infections
remains a high priority task.”
Acute HCV infection continues to occur
in the United States
• Sexual Transmission of Hepatitis C Virus Among HIVInfected Men Who Have Sex with Men --- New York
City, 2005--2010
• Acute Hepatitis C Virus Infections Attributed to
Unsafe Injection Practices at an Endoscopy Clinic --Nevada, 2007
• Hepatitis C Virus Infection Among Adolescents and
Young Adults --- Massachusetts, 2002--2009
MMWR May 16, 2008 / 57(19);513-517; MMWR July 22, 2011 / 60(28);945-950;
MMWR; May 6, 2011 / 60(17);537-541
Since 2007, more Americans die from HCV than HIV
infection
•
National multiple-cause mortality data
Mortality rates of HBV, HCV, and HIV;
United States 1999-2007
'By 2007 hepatitis C-associated deaths
had overtaken HIV as a cause of
mortality in the United States. To
achieve declines in mortality similar to
those seen with HIV will require new
policy directions and commitment to
detect and link infected persons to care
and successful treatment‘
•
Co-morbidities associated with
increased odds ratio of mortality
–
–
Alcohol related
(4.6;HCV and 3.7;HBV)
HIV co-infection
(1.8;HCV and 4.0;HBV)
Holmberg SD , et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 243
Future Burden of Hepatitis C Related
Morbidity and Mortality in the US
• Markov model of health
outcomes • Of 2.7 M HCV infected persons in
primary care
— 1.47 M will develop cirrhosis
— 350,000 will develop liver cancer
— 897,000 will die from HCV-related
complications
• Incur expenses
— $24.7 productivity losses
— $179.53 per person in primary care
— $33.3 billion medical costs
1 Rein
et al Dig Liver Dis 2010
Treatment of chronic hepatitis can save lives
SVR for HCV reduces HCC, ESLD, and death
Survival in HCV GT 1 VA members after treatment
Backus Clin Gastro 2011; Imazeki Hepatology 2003; Shiratori Ann Intern Med 2005; Veldt et
al Ann Intern Med 2007; Berenguer Hepatology 2009;
HCV treatment with IFN/RBV is not effective due to
contraindications: National VA cohort
Kramer et al. J Hepatol. 2011 Jul 12. [Epub ahead of print]
HCV treatment: Injection drug
users
SH Mehta, et al. J Community Health 33 (2008), pp. 126–133
Birth Cohort Screening to be adopted in the US --July 2012
1999-2002 NHANES
6%
5%
4%
3%
2%
1%
Age Group (years)
Armstrong et al. Ann Intern Med, 2006
55+
50-54
45-49
40-44
35-39
0%
20-34
Overall 4.3%
Men 6.2%
Blacks 9.4%
Black men 13.6%
Women
6-19
65.6% born in
1945-1964
Men
7%
ALL
-
8%
Prevalence of an -HCV
HCV prevalence
- chronic 1.3% (3.2 mil)
DHHS/CDC Response ~ 2012
• July 2012: Revise CDC guidelines to promote early detection
•
•
•
•
Confirm active HCV infection (HCV PCR, core antigen)
Routine and periodic testing of persons with transmission risks
( e.g. IDU)
Routine one –time testing of subpopulations of high prevalence
[e.g., birth cohort 1946-1964] ) of HCV disease
– Integrate HCV and HIV screening in STD clinics, drug outreach, prisons,
• Improve training of clinicians in viral hepatitis screening, management,
and care
• Support models and standards of care that promote linkage of HCV
screening with medical management and treatment services
Brown H, J Clin Gastroenterol 2008
US Investment in Viral Hepatitis Lags Far Behind
Edlin Nature 2011
Viral Hepatitis: Prevention and
Control
The Global
Perspective
HBV and HCV is a leading cause of
death: A global perspective
7
5
HIV
HBV + HCV
Measles
RSV, Rota
Flu
Dengue
4
HPV
Log10 Global Death Rate
6
3
2
1
Tobacco
Malaria
Road accidents
Non-HIV TB
Hospital infection
Suicide
West Nile
SARS
Ebola
Polio
Hanta
vCJD
Caused by Viruses
Other Causes
Global Death Rate
Adapted by permission from Macmillan Publishers Ltd: Nature Medicine.
Weiss RA, et al;10(12 suppl):S70-S76, copyright 2004.
Burden of Chronic Viral Hepatitis
HCV
HBV
350,000,000
infected
Cirrhosis
Chronic hepatitis
170,000,000
infected
HCC
www.ncbi.nlm.nih.gov; Yu X Virology 2007
Burden of Chronic Viral Hepatitis
HCV
HBV
Chronic hepatitis
Cirrhosis
446,000 deaths
HCC
Perz, J Hepatol 2006;
www.ncbi.nlm.nih.gov; Yu X Virology 2007
Burden of Chronic Viral Hepatitis
HCV
HBV
Chronic hepatitis
Cirrhosis
Perz J Hepatol 2006;
www.ncbi.nlm.nih.gov; Yu X Virology 2007
HCC
483,000 deaths
Burden of Chronic Viral Hepatitis
929,000
Deaths/year
HCV
HBV
Chronic hepatitis
Cirrhosis
HCC
WHO 2008; Perz J Hepatol 2006; www.ncbi.nlm.nih.gov; Yu X Virology 2007
Worldwide HCV Prevalence
Hepatitis C Deaths (2008)
Hepatitis B Deaths (2008)
Absolute Poverty (< 2 dollars day)
Prevention: Unsafe health-care
injections
• World wide, unsafe
injections account for
an estimated:
Dangerous practices at Las Vegas
endoscopy clinic called 'baffling'
– 30% of hepatitis B
infections
– 24% of hepatitis C
infections
– 27% of liver cancer
– 24% of liver cirrhosis
deaths
http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_part2.pdf
Prevention: Injection drug use
Global Heroin Use (UNDOC)
Prevention: HBV vaccine
• WHO position paper on
Hepatitis B vaccines
• Infant programs in 177
countries
– 69% of 2008 birth cohort
received 3 doses
• Only 27% within 24 hours
– All infants should receive
their first dose as soon
as possible after birth (<
12)
Decreased Incidence of HCC in Hepatitis B
Vaccinees: A 20-Year Follow-up Study
Group
Personyears
No.
of
HCCs
RR
(95% CI)
No
Vaccine
78,496,404
444
1.00 (referent)
Vaccine
37,709,340
64
0.31
(0.24 -0.41)
Chang M-H, et al J Natl Cancer Inst 2009
Can we make an effective HCV
vaccine?
• Challenges parallel to
HIV
– Highly diverse virus
– Unsafe to use live
attenuated or killed virus
– Vectors to deliver viral
antigens in a system that
induces robust innate
and adaptive immune
responses
• Preexisting vector
immunity limits responses
rs12979860 C IL-28B allele associated with higher
probability of natural clearance of HCV
Thomas DL, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009; 461(7265):798
Protection from Persistent HCV
p = 0.001 compared to initial infection
Osburn et. al. Gastroenterolgy 2010;138:315–324
(P =.001)
Shorter duration of viremia during
reinfection
Osburn et. al. Gastroenterolgy 2010;138:315–324
Preventing pre-existing anti-vector immunity from
limiting vaccine efficacy
• Okairos search for novel adenoviral strains
in chimpanzees worldwide
• Goals: Discover adenoviral vectors that are
• Highly immunogenic
• Easily manufactured to high titers
• Not stimulating cross reactive immunity
(humans rarely exposed)
• Success:
• Adenoviruses derived from chimpanzees
(ChAd) differ from human adenovirus
primarily in hexon (surface) proteins, making
Ab cross reactivity low
• many are highly immunogenic
HCV Vaccine Healthy Volunteer Trial
• AdCh3NS and Ad6NS are highly potent (> 1400
SFU/million PBMC; IFN- ELISpot) following a single
injection.
• At the highest dose all individuals responded to
vaccination.
• The majority of subjects developed responses against
multiple HCV proteins.
• Polyfunctional CD4 and CD8+ T cells are induced.
• AdCh3NS and Ad6NS are safe and well tolerated at all
tested doses.
Barnes et. al. Science Translational Medicine 2012
HLA class-I pentamer
(KLSGLGINAV)
High frequencies of HCV Specific CD8 T cells
10
5
10
0%
10
5
4
10
10
3
10
2
0
7.18%
10
5
4
10
10
3
10
2
0
0
10
2
10
3
10
4
10
5
0.83%
10
5
4
10
10
3
10
2
0
0
10
2
10
3
10
4
10
5
6.24%
10
5
4
10
4
10
3
10
3
10
2
10
2
0
0
10
2
10
3
10
4
10
5
1.52%
0
0
10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
CD8+
% Pentamer positive CD8
(KLSGLGINAV)
10
B
1
0.1
0.01
4 weeks post prime
Ad1 prime
(TW4 or 8)
(TW0)
Barnes et. al. Science Translational Medicine 2012
Ad2 boost
(TW 8 or 24)
4 weeks post boost
(TW 12 or 28)
Final time point
(TW 36 or 52)
HCV Prophylactic Vaccine Based on Sequential
Use of AdCh3and MVA with NS
• Cross reactivity of AdCh3 with human antiadenovirus Abs is 12%
• MVA boosts well in Phase I trials
• Double-blinded, randomized, placebocontrolled two stage study.
• Subjects: HCV Ab and RNA negative, active
IDU’s at high risk for HCV, 18 -45 y.o.
• Two Sites (UCSF, JH)
W0
W8
AdCh3
2.5 x1010vp
MVA
1.8x108pfu
W = week
W50
= test immune response
HCV treatment: Heterogeneity in
Europe
J Hepatol. 2008 Oct;49(4):528-36.
HCV Treatment: Limited
availability in many regions
Progress toward HCV eradication will
be limited by delivery
Thomas Lancet 2010
Improvements in HCV Detection, Care and
Therapy Needed to Reduce Future Increases in
HCV Mortality
-8%
-18%
Deaths
-37%
Deuffic-Burban, J Viral Hepatitis 2007.
Difficult challenges to addressing the global
burden of disease due to viral hepatitis
• Societal
–
–
–
–
Poverty
Competing priorities (e.g., HIV, malaria, Tb)
Indifference (e.g., IDUs)
Health systems – reimbursement; doctors
• Individual
– Medical and psychiatric comorbidities
– Indifference (asymptomatic disease)
• Therapeutic
–
–
–
–
Cost
Toxicity
Effectiveness
Delivery (injection, cold-chain packaging )
Geopolitical Solutions are needed
• HIV is well funded
because there is
political will
–
–
–
–
public health importance
economic impact
celebrities
advocacy groups
Expanding Global Update of HIV Treatment
HIV related mortality was reduced
in countries with PEPFAR programs
Bendavid Ann Intern Med 2009
Global AIDS-related Deaths
Estimated number of AIDS-related deaths with and
without antiretroviral therapy, globally, 1996–2008
3.0
Number (millions)
2.5
2.0
1.5
1.0
0.5
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
No antiretroviral therapy
At current levels of antiretroviral prophylaxis
UNAIDS: 2009 AIDS epidemic update; UNAIDS.org
Prevention and control depends on
political and societal commitment
• Prevention
– Safer needle use, no reuse, and/or abuse
– Vaccine
• Control
– Detection
– Treatment can cure infected individuals
• Safe, oral therapies
• Lower cost
– Treatment can reduce transmission by curing
active IDUs