NIH Presentation

1. Epidemiology and Prevention
Strategies for HCV and HEV
Kenrad E Nelson, MD
Johns Hopkins University
Baltimore, Maryland, USA

2. Epidemiology of HCV
1. An estimated 185 million persons have been
infected with HCV globally
2. An estimated 70‐80% developed chronic HCV
infection
3. Over 350,000 deaths from HCV each year
4. Progression to cirrhosis, end stage liver
disease or hepatocyte carcinoma occurs over
many years in an estimated 20% of patients
with chronic HCV

6. HCV in Egypt
1. Between 1963 and 1980 a mass campaign of 12‐16 weeks of
intravenous injections with antimony salts were given to eradicate
schistosomiasis
2. Treatment targeted children and adults living in endemic areas
3. Program stopped in 1982 due to availability of praziquantel
4. Since then the transmission of HCV has continued through
a. Injections
b. Blood transfusion
c. Dental treatment
d. Surgery
e. Circumcision
f. Sexual transmission
5. Over 95% of HCV are genotype 4

25. Prevention Strategies for HCV
1. Screen all injection drug users frequently
(annually?)
2. Screen patients with STDs or HIV; Use rapid test
so follow up HCV RNA can be assessed
3. Harm reduction and counseling IDUs to avoid
sharing needle and works (cotton, water etc)
4. Screen blood donors with EIA and NAT
5. Ensure safe injections, diabetes testing etc?
6. Eventually treatment with DAA may help?
“treatment as prevention”

26. Guidelines for the Screening, Care and
Treatment of Persons with Hepatitis C Infection
WHO, April 2014
An expert committee of WHO offered the following
guidelines to low‐middle income countries for the control
of HCV.
A. Screening for HCV infection
1. Screen individuals who are in a risk population with high
HCV prevalence or with high risk behavior
2. Continue the diagnosis of a positive ELISA with NAT
B. Care of persons with HIV
3. Screen for alcohol use and counseling to reduce alcohol
4. Assess degree of fibrosis cirrhosis with biochemical tests,
APRI or F1B4

27. Guidelines for the Screening, Care and Treatment of
Persons with Hepatitis C Infection
WHO, April 2014 (cout’d)
C. Treatment of HCV
5. All adults and children with chronic HCV, including
IDUs should be assessed for antiviral treatment
6. Treatment with pegylated interferon ribavirin
7. Treat HCV Genotype 1 patients with: telaprevir or
boceprevir plus pegylated IFN and RBV
8. Treat with sofosbuvir with or without pegylated IFN
(depending on the HCV genotype) 1, 2, 3 and 4 who
cannot tolerate interferon
9. Treat with simeprevir and pegylated IFN for persons
with HCV 1b or 1a without the Q80k polymorphism

28. Populations at Increased Risk of HCV
(WHO Report, 2014)
1. PWIDs are at the highest risk, global prevalence = 67%
2. Recipients of infected blood products or invasive
procedures with inadequate infection control
3. Children born to mothers with HCV (trans rate = 4‐5%;
if HIV pos = 12‐20%)
4. Persons with HCV positive sex partners, esp. MSM or
HIV pos partners
5. Persons with HIV infection
6. Persons who have used intranasal drugs
7. Persons with tattoos or piercings

29. Treatment of HCV as Prevention – A
Modeling Case Study in Vietnam (Durier
et al. PlosOne, 2012)
1. Treatment of 25%, 50% and 75% HCV infected IDUs
who had been infected for 4 years, reduced the HCV
prevalence after 11 years by 21%, 57% and 50%.
2. Treatment of 50% of IDUs earlier, ie. Infected for 3, 2,
or 1 year, reduced population prevalence by 46%, 60%
and 85%.
3. With earlier treatment – for every 100 treatment
courses 50 (3 yrs), 61 (2 yrs) and 94 (1 yr) new
infections could be averted.
4. The model assumed low use of methadone and NS
program.

30. Barriers to Treatment as Prevention of
HCV
1. Difficult to identify and treat HCV + IDUs and
Asymptomatic HCV + Non‐IDUs
2. Cost of antiviral drugs – likely to decrease
substantially. (Sofosbovir now 900 for 12 wk
course in Egypt)
3. HCV re‐infection occurs and could increase?
4. Comprehensive harm reduction services
essential to prevent transmission and re‐
infection
5. Education and counseling of all HCV patients
and their contacts.

33. Source: R. Purcell (2009)

34. N ~ 30,000 cases

35. Unusual Features of 1955 Delhi
Hepatitis Outbreak
1. High clinical attack rate in adults and low
illness rate in children
2. Limited secondary person to person
spread
3. High mortality rate in pregnant women
(65 fatal cases; 30 in pregnant women)

37. Source: Krain, Nelson, Labrique 2014

38. HEV in the Indian Subcontinent

39. Source: R. Purcell (2009)
“Enterically Transmitted,
Non-A, Non-B Hepatitis”
1980

40. Mikhail Balayan, MD
1983

44. Estimated Global Burden of HEV Genotypes
1 and 2 infections in Asia and Africa, 2005
(Rein D et al Hepatology 2012)
• HEV Seroprevalence and annual
incidence of 1/ and 2 infections in Asia and
Africa in 2007 were estimated from
literature(GBD, 2010, WHO)
• HEV incidence=20.1 million cases.
• 3.4 million symptomatic cases
• 70,000 deaths; 3,000 still births
• Deaths; non-pregnant 0.019, pregnant
0.198

45. Global distribution by “Endemicity”
Source: CDC 2011

49. Global Distribution of HEV GT’s

50. Figatellu
 Traditional sausage from Corsica, France
 Made with pig liver
 Often eaten raw or undercooked
 30 million sausages purchased every year in France

51. Mortality During HEV Epidemics - What is
needed?
1. Two HEV vaccine have been developed and found to be
effective in preventing hepatitis in clinical trials; one,
HEV-239, Hecolin is only available and licensed in
China.
2. Trials of immunogenicity and safety for mother and
fetus and efficacy are needed in pregnant women in
countries where HEV genotype 1 – infections are
endemic.
3. If found to be effective, the vaccine should be licensed
and available in countries in South Asia and Africa
where HEV occurs in epidemics.
4. GAVI should be asked to provide support for HEV
vaccine during human infection emergencies.

52. Public Health Importance of
Hepatitis E Virus (HEV)
1. HEV is likely the major cause of epidemic
hepatitis globally
2. The increased mortality among pregnant
women has been repeatedly documented
3. It is also a significant food-borne pathogen in
developed countries with an animal reservoir
4. HEV is likely preventable with improved
sanitation, adequate cooking of food and a
vaccine

53. Prevention vs. treatment of HEV in high risk
population
1. Pregnant women:
a. Prevention:
1. Vaccine effective prior to intervention
2. Avoid contaminated water, food (difficult)
b. treatment:
1. Ribavirin and Interferon cannot be given to pregnant women
2. Transplant patients (and other immune‐compromised
pts)
a. Prevention:
1. Vaccine could be given prior to transplant and immunosuppressive drugs;
efficacy likely poor after transplant
2. Avoid uncooked food, esp. pork, shellfish
b. Treatment:
1. Ribavirin proven effective
2. Decrease drugs, e.g. tacrolimus

54.  Acknowledgements;
 NIAID: Rajen Koshy CDC:
 Robert Purcell John Ward
 Ron Engle Scott Holmberg
 Johns Hopkins University
 Alain Labrique John Ticehurst
 Mark Kuniholm David Thomas
 Lisa Krain Dave Vlahov
 Brittany Kmush

57. Hepatitis C Virus Infection in IDUs
1. HCV transmission by needlestick 10 times more
frequent than HIV.
2. HCV prevalence among IDUs: worldwide = 50‐90%
3. Therefore IDUs who share syringes or “works” are
frequently exposed to HCV
4. In countries with active harm reduction programs HIV
incidence has declines; however only modest declines
in HCV incidence were seen
5. About 20‐30% of IDUs spontaneously clear HCV;
however HCV re‐infection can occur.

58. HCV Treatment for Injection Drug
Users
1. Because of co‐morbidity, expected poor
compliance and HCV re‐infection risk, NIH and
EASL committees recommended not treating
active IDUs for HCV.
2. However, experience with SVR rates of selected
IDUs who accepted HCV therapy with PEG‐
IFN/RBV were similar to non‐IDUs, ie, 30‐50%
3. HCV re‐infection occurred in some IDUs after
SVR, however the re‐infection rates were lower
than expected (i.e. 1‐2/100 pyrs)

59. HCV Treatment for Injection Drug
Users (Continued)
4. If HCV infected IDUs had access to Harm
Reduction Services, high rates of HCV re‐infection
could be prevented.
5. With the availability of oral therapy with 12
weeks of DNA drug, “treatment of HCV in IDUs may
be a priority to control population incidence, i.e.
“Treatment as Prevention””
6. Which IDUs should be priority – those using
MMT and NSE or non‐users? This is an ethical issue.

60. HCV Incidence Among IDUs in the
ALIVE Study, Baltimore
1. 2946 IDUs without AIDS enrolled in 1988‐1989 to study HIV risk behavior
2. Additional cohorts enrolled:
a. 1994‐1995 (n=399)
b. 1998 (n=244)
c. 2005‐2008 (n=875)
3. Subjects who were HIV and HCV negative were followed for incident infections
4. HIV incidence in successive cohorts in year after enrollment:
a. 1988‐1989: 5.5/100 pyrs
b. 1994‐1995: 2.0/100 pyrs
c. 1998: 0/100 pyrs
d. 2005‐2008: 0/100 pyrs
5. HCV incidence in successive cohorts in year after enrollment
a. 1998‐1999: 22.0/100 pyrs
b. 1994‐1995: 17.7/100 pyrs
c. 1998: 17.9/100 pyrs
d. 2005‐2008: 7.8/100 pyrs
6. Harm Prevention Program was available in Baltimore

63. Prevention Strategies for HCV
1. Screen all injection drug users frequently
(annually?)
2. Screen patients with STDs or HIV; Use rapid test
so follow up HCV RNA can be assessed
3. Harm reduction and counseling IDUs to avoid
sharing needle and works (cotton, roster etc)
4. Screen blood donors with EIA and NAT
5. Ensure safe injections, diabetes testing etc?
6. Eventually treatment with DAA may help?
“treatment as prevention”

64. 597
418
86
56
26 5
0
100
200
300
400
500
600
700
Number of participantsTreatment experience in ALIVE, 1988-2006
HCV Ab Aware of Discussed Agreed Initiated Sustained
positive treatment with provider to treatment treatment virologic
response
Of the 26, 50% received treatment through a
research study
Rate of treatment did not increase from
1998-2006
Factors associated with initiating treatment:
male, health insurance, no drug or alcohol
use
Mehta SH et al J Comm Health 2007

65. HCV treatment effectiveness among HIV/HCV co-
infected patients in regular HIV care
845
277
185
125
69
29 6
0
100
200
300
400
500
600
700
800
900
In regular HIV
care
Referred Keeps
appointment
Pre-treatment
evaluation
Treatment
eligible
Treatment
initiated
Sustained
virologic
response
Mehta SH et al, AIDS, 2006
Predictors of referral:
- High CD4, low HIV VL, on ART
- No active substance use
- Elevated liver enzymes
- Being in psychiatric care
Predictors of treatment initiation:
-Advanced fibrosis
-non-African-American race
Being in methadone did not predict referral,
attendance or treatment initiation

66. Major Scientific Advances Toward
curing Hepatitis C Virus Infection
1. Infection of chimpanzees and creating a library of
DNA clones from infectious plasma (1989).
2. Discovery that the HCV viral genome was a
positive stranded RNA virus with cytoplasmic
replication.
3. Construction of sub‐genomic replicons harboring
the viral non‐structural proteins (NS3‐5)so that
Antiviral Drugs could be tested.
4. Discovery of a gt‐2 HCV viral isolate that
efficiently replicated in a human hepatoma cell
line.

67. Major Scientific Advances
5. Discovery that Pegylated Interferon and Ribavirin
treatment for 24‐48 weeks could lead to cure of
about 50% of chronic HCV infections
6. Successful control of replication anti‐viral therapy
targeting several non‐overlapping enzymes, e.g.
Protease, Polymerase etc‐ adapted to HCV
7. Decision of FDA to permit licensure of new HCV
antivirals without standard of care comparator.,
RBV& Peg‐Interferon

68. Challenges to the Control of Hepatitis
C using Direct Acting Antiviral Drugs
1. Identifying persons with chronic HCV: Global
Estimate= 170 million
2. Current High cost of DAA drugs
3. Re‐infections with HCV after their cure in
persons with continued exposure

69. Will cost of Newly Licensed Direct
Acting Anti‐HCV Drugs Prevent their
effective Use?
1. Gilead Pharm paid 11 billion dollars to
acquire the company that developed Sovaldi
(Sofosbavir)
2. The cost of a 12 week course is $84,000
3. J and J markets Olysio (Simeprevir) at a cost
of $66,000 for a 12 week course
4. Although these 2 drugs are over 90%
effective in curing Chronic HCV the cost is
$150,000

70. Treatment Costs for Direct Acing Anti‐
HCV Drugs ‐‐‐ Pushbacks
1. Gilead has negotiated a reduced price of $900.00 a
99% reduction for a 12 week course of Sovaldi
(Sofosbavir) with Egypt, the country with the highest
HCV prevalence in the world.
2. Gilead has announced plans to license Sovaldi to 3‐4
India firms for generic sales to 60 developing nations.
But this doesn’t include Russia, China, Ukraine (and
probably many countries in the middle east)
3. Will the cost of these drugs prevent their wide use for
treatment and prevention of HCV globally.

71. Antiviral Treatment as Prevention HIV
vs. HCV
1. AIDS Clinical Trial Study 052 found a hazard ratio
of 0.04 (95% CI 0.01‐0.27) for transmission of
HIV in 1763 discordant couples (Cohenms,
NEJM, 2011).
2. Spread of HCV by needle stick 10 times greater
risk than HIV; HCV sexual transmission rare.
3. Can HCV transmission among IDUs and non‐
IDUs be prevented by antiviral therapy of HIV
positives?

72. HCV Treatment as Prevention among
IDUs
1. Therapy with infection + Ribavirin in Injection drug
users difficult because of toxicity of drugs, co‐
morbidity
2. SVR similar among IDUs and non‐IDUs, ie. 40‐50% IFN
+ RBV and acute HCV, ie. 68% SUR
3. Oral direct acting antiviral drugs – 85‐100% SVR. No
data yet on IDUs
4. HCV re‐infection rate after SVR in IDUs 3.2‐5.3 per 100
pyrs
5. Prior to therapy 7.4‐25.0 per 100 pyrs
6. Counseling and harm reduction with antiviral therapy
among IDUs critical

73. Treatment of HCV as Prevention – A
Modeling Case Study in Vietnam (Durier
et al. PlosOne, 2012)
1. Treatment of 25%, 50% and 75% HCV infected IDUs
who had been infected for 4 years, reduced the HCV
prevalence after 11 years by 21%, 57% and 50%.
2. Treatment of 50% of IDUs earlier, ie. Infected for 3, 2,
or 1 year, reduced population prevalence by 46%, 60%
and 85%.
3. With earlier treatment – for every 100 treatment
courses 50 (3 yrs), 61 (2 yrs) and 94 (1 yr) new
infections could be averted.
4. The model assumed low use of methadone and NS
program.

74. Barriers to Treatment as Prevention of
HCV
1. Difficult to identify and treat HCV + IDUs and
Asymptomatic HCV + Non‐IDUs
2. Cost of antiviral drugs – likely to decrease
substantially. (Sofosbovir now 900 for 12 wk
course in Egypt)
3. HCV re‐infection occurs and could increase?
4. Comprehensive harm reduction services
essential to prevent transmission and re‐
infection
5. Education and counseling of all HCV patients
and their contacts.

75. Reported Case-Fatality Rates (CFR) from
ET-non-A/non-B (HEV) Hepatitis 1973-1994,
12 outbreaks SE Asia
No Outbreaks CFR CFR(Preg
women)
Nepal 3 0 – 7% 5 – 21%
India 7 0.3 – 5.0% 7 – 39%
Pakistan 2 0.2 – 1.0% 5 – 11%
Myanmar 2 1.0 – 3.5% 12 – 18%

76. Since then…
1991: Virus cloned and sequenced
1993: HEV in Mexico (new genotype)
1995: HEV identified in Pigs
1995-1999: High seroprevalence of anti-
HEV in developed countries
2000-2004: HEV identified in deer, wild
game
2005: Vaccine Trial: > 95% Efficacy
2008: Avian-HEV / Autochthonous HEV 

77. Virus Characteristics
• HEV is a spherical, non-enveloped, single-stranded RNA virus
• Approximately 27-34nm in diameter
• Classified as Hepeviridae (genus Hepevirus)
• May be unstable in external environment / labile
Source: Meng 2008 / Emerson 2007

79. Global Distribution of HEV GT’s

81. Source: R. Purcell 2008

82. Estimated Global Burden of HEV Genotypes
1 and 2 infections in Asia and Africa, 2005
(Rein D et al Hepatology 2012)
• HEV Seroprevalence and annual
incidence of 1/ and 2 infections in Asia and
Africa in 2007 were estimated from
literature(GBD, 2010, WHO)
• HEV incidence=20.1 million cases.
• 3.4 million symptomatic cases
• 70,000 deaths; 3,000 still births
• Deaths; non-pregnant 0.019, pregnant
0.198

86. Epidemics of HEV in Displaced
Persons – Humanitarian
Emergencies
1. Namibia (Okavango Region)–1983
201 cases
2. Somalia January 1985-Sept, 1986
2,000 cases, 87 deaths, 40 (46%) of
deaths in pregnant women
3. Darfur, Sudan July-Dec 2004, 2621
cases, 45 deaths (18 preg. women)
4. Kitgum District, Uganda Oct, 2007
10,196 cases; 160 deaths

87. Hepatitis E Virus Epidemics in Displaced
Persons in Humanitarian Disasters.
Darfur Sudan, 2006:
• In July–December, 2004: 2621 cases of HEV
hepatitis–78,000 persons (3.3% AR) – previous
pop=6,000
• 253 hospital admissions:
72 hepatic encephalopathy
45 deaths (CFR=17.8%)
3. 220/1133 pregnant women were jaundiced
(CFR=19.4%)
- Mortality 18/220=8.2%
4. Mortality non-pregnant women=2/2401=1.1%

92. Mortality Rate (HEV in Pregnancy)
Labrique et al., M/S In Preparation, 2011

94. Pathogenesis in Pregnancy
Source: Navaneethan, 2003

95. Minimum Costs for Producing Hepatitis C Direct
Acting Antivirals for Use in Large Scale treatment
Access Programs in Developing Countries
Andrew Hill et al Clin Infect Dis 2014
In this paper, these pharmacologists analyzed the costs
of materials and manufacturing costs of several direct
acting antivirals in development to treat HCV if 1‐5
million subjects were treated. They concluded: “Within
the next 15 years, large‐scale manufacture of two or
three drug combinations of HCV DAAs is feasible, with
minimum target prices of US$100‐250 per 12 week
treatment course. These low prices could make
widespread access to HCV treatment in low and middle
income countries a realistic goal.”

97. Epidemics of HEV in Displaced
Persons – Humanitarian
Emergencies
1. Namibia (Okavango Region)–1983
201 cases
2. Somalia January 1985-Sept, 1986
2,000 cases, 87 deaths, 40 (46%) of
deaths in pregnant women
3. Darfur, Sudan July-Dec 2004, 2621
cases, 45 deaths (18 preg. women)
4. Kitgum District, Uganda Oct, 2007
10,196 cases; 160 deaths

98. Hepatitis E Virus Epidemics in Displaced
Persons in Humanitarian Disasters.
Darfur Sudan, 2006:
• In July–December, 2004: 2621 cases of HEV
hepatitis–78,000 persons (3.3% AR) – previous
pop=6,000
• 253 hospital admissions:
72 hepatic encephalopathy
45 deaths (CFR=17.8%)
3. 220/1133 pregnant women were jaundiced
(CFR=19.4%)
- Mortality 18/220=8.2%
4. Mortality non-pregnant women=2/2401=1.1%

99. Public Health Importance of
Hepatitis E Virus (HEV)
1. HEV is likely the major cause of epidemic
hepatitis globally
2. The increased mortality among pregnant
women has been repeatedly documented
3. It is also a significant food-borne pathogen in
developed countries with an animal reservoir
4. HEV is likely preventable with improved
sanitation, adequate cooking of food and a
vaccine

100. HEV has significant
public health importance
• Impact in Pregnancy
– 15 – 40% CFR
– Cholestasis / ALF / DIC
– Fetal loss / Neonatal
mortality
• Increasing Exposures
– Tourism to developing
countries
– Conflict (Military,
Refugees, Host Nations)
Photos: AFP / AP

101. Recombinant HEV Vaccine
Phase-3 Trial in China
• Vaccine: ORF-2 subunit HEV vaccine
produced in E. coli
• “Placebo”: HBV vaccine
• Population: 97,356 HEV neg persons from
central China enrolled 48,693 (U), 48,663
(P)
• Vaccine at 0, 1, 6 months
• Outcome: Clinical hepatitis due to HEV-19
month follow-up

102. HEV Vaccine Trial in China
Results
• 23 cases of HEV; all Igm HEV pos, 22
HEV-RNA pos
• 22 cases in placebo, 1 case in vaccine
• 15 HEV cases in 12 months after 3rd
vaccine dose, all 15 in placebo
• Vaccine efficacy: 100% (CI 72.1-100) for
subjects with 3 doses
• Vaccine efficacy: 95.5% (CI 60.3-99.4%)
for subjects ≥ 1 dose

103. Prevention of Fulminant Hepatitis and
Mortality During HEV Epidemics ‐ What is
needed?
1. Two HEV vaccine have been developed and found to be
effective in preventing hepatitis in clinical trials; one, HEV‐
239, Hecolin is only available and licensed in China.
2. Trials of immunogenicity and safety for mother and fetus
and efficacy are needed in pregnant women in countries
where HEV genotype 1 – infections are endemic.
3. If found to be effective, the vaccine should be licensed
and available in countries in South Asia and Africa where
HEV occurs in epidemics.
4. GAVI should be asked to provide support for HEV vaccine
during human infection emergencies.

104. Prevention vs. treatment of HEV in high risk
population
1. Pregnant women:
a. Prevention:
1. Vaccine effective prior to intervention
2. Avoid contaminated water, food (difficult)
b. treatment:
1. Ribavirin and Interferon cannot be given to pregnant women
2. Transplant patients (and other immune‐compromised
pts)
a. Prevention:
1. Vaccine could be given prior to transplant and immunosuppressive drugs;
efficacy likely poor after transplant
2. Avoid uncooked food, esp. pork, shellfish
b. Treatment:
1. Ribavirin proven effective
2. Decrease drugs, e.g. tacrolimus