Epidemiology and Prevention Strategies for HCV and HEV

Kenrad E Nelson, MDJohns Hopkins UniversityBaltimore, Maryland, USA

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 year4. Progression to cirrhosis, end stage liver 

disease or hepatocyte carcinoma occurs over many years in an estimated 20% of patients with chronic HCV

HCV in Egypt1. 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 areas3. Program stopped in 1982 due to availability of praziquantel4. Since then the transmission of HCV has continued through

a. Injectionsb. Blood transfusionc. Dental treatmentd. Surgerye. Circumcisionf. Sexual transmission

5. Over 95% of HCV are genotype 4

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 NAT5. Ensure safe injections, diabetes testing etc?6. Eventually treatment with DAA may help? 

“treatment as prevention”

Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection

WHO, April 2014An 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 NATB. Care of persons with HIV

3. Screen for alcohol use and counseling to reduce alcohol4. Assess degree of fibrosis cirrhosis with biochemical tests, 

APRI or F1B4

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 ribavirin7. Treat HCV Genotype 1 patients with: telaprevir or 

boceprevir plus pegylated IFN and RBV8. 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  

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 control3. 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 partners5. Persons with HIV infection6. Persons who have used intranasal drugs7. Persons with tattoos or piercings

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.

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 wkcourse 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.

Source: R. Purcell (2009)

N ~ 30,000 cases

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)

Source: Krain, Nelson, Labrique 2014

HEV in the Indian Subcontinent

Source: R. Purcell (2009)

“Enterically Transmitted, Non-A, Non-B Hepatitis”

1980

Mikhail Balayan, MD

1983

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

Global distribution by “Endemicity”

Source: CDC 2011

Global Distribution of HEV GT’s

Figatellu

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

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.

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

Prevention vs. treatment of HEV in high risk population

1. Pregnant women:a. Prevention:

1. Vaccine effective prior to intervention2. 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 transplant2. Avoid uncooked food, esp. pork, shellfish

b. Treatment:1. Ribavirin proven effective2. Decrease drugs, e.g. tacrolimus

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

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 HCV4. 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.

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)

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.

HCV Incidence Among IDUs in the ALIVE Study, Baltimore

1. 2946 IDUs without AIDS enrolled in 1988‐1989 to study HIV risk behavior2. 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 infections4. HIV incidence in successive cohorts in year after enrollment:

a. 1988‐1989: 5.5/100 pyrsb. 1994‐1995: 2.0/100 pyrsc. 1998:            0/100 pyrsd. 2005‐2008:  0/100 pyrs

5. HCV incidence in successive cohorts in year after enrollmenta. 1998‐1999: 22.0/100 pyrsb. 1994‐1995: 17.7/100 pyrsc. 1998:            17.9/100 pyrsd. 2005‐2008:  7.8/100 pyrs

6. Harm Prevention Program was available in Baltimore

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 NAT5. Ensure safe injections, diabetes testing etc?6. Eventually treatment with DAA may help? 

“treatment as prevention”

597

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86 56 26 50

100

200

300

400

500

600

700

Num

ber o

f participa

nts

Treatment experience in ALIVE, 1988-2006

HCV Ab Aware of Discussed Agreed Initiated Sustainedpositive 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

HCV treatment effectiveness among HIV/HCV co-infected patients in regular HIV care

845

277

185125

6929 6

0

100

200

300

400

500

600

700

800

900

In regular HIVcare

Referred Keepsappointment

Pre-treatmentevaluation

Treatmenteligible

Treatmentinitiated

Sustainedvirologicresponse

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

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.

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 infections6. Successful control of replication anti‐viral therapy targeting several non‐overlapping enzymes, e.g. Protease, Polymerase etc‐ adapted to HCV7. Decision of FDA to permit licensure of new HCV antivirals without standard of care comparator., RBV& Peg‐Interferon

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 drugs3. Re‐infections with HCV after their cure in 

persons with continued exposure

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 $84,0003. J and J markets Olysio (Simeprevir) at a cost 

of $66,000 for a 12 week course4. Although these 2 drugs are over 90% 

effective in curing Chronic HCV the cost is $150,000

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.

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?

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 pyrs6. Counseling and harm reduction with antiviral therapy 

among IDUs critical

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.

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 wkcourse 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.

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%

Since then…1991: Virus cloned and sequenced1993: HEV in Mexico (new genotype)1995: HEV identified in Pigs1995-1999: High seroprevalence of anti-

HEV in developed countries2000-2004: HEV identified in deer, wild

game2005: Vaccine Trial: > 95% Efficacy2008: Avian-HEV / Autochthonous HEV

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

Global Distribution of HEV GT’s

Source: R. Purcell 2008

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

Epidemics of HEV in Displaced Persons – Humanitarian

Emergencies1. Namibia (Okavango Region)–1983

201 cases2. 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

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 encephalopathy45 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%

Mortality Rate (HEV in Pregnancy)

Labrique et al., M/S In Preparation, 2011

Pathogenesis in Pregnancy

Source: Navaneethan, 2003

Minimum Costs for Producing Hepatitis C Direct Acting Antivirals for Use in Large Scale treatment 

Access Programs in Developing CountriesAndrew 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.”

Epidemics of HEV in Displaced Persons – Humanitarian

Emergencies1. Namibia (Okavango Region)–1983

201 cases2. 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

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 encephalopathy45 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%

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

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

Recombinant HEV VaccinePhase-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

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

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.

Prevention vs. treatment of HEV in high risk population

1. Pregnant women:a. Prevention:

1. Vaccine effective prior to intervention2. 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 transplant2. Avoid uncooked food, esp. pork, shellfish

b. Treatment:1. Ribavirin proven effective2. Decrease drugs, e.g. tacrolimus