the hepatitis c virus epidemic in egypt dr. f. dewolfe miller, face john a. burns school of medicine...

The Hepatitis C Virus Epidemic in Egypt

Dr. F. DeWolfe Miller, FACE

John A. Burns School of Medicine Department of Tropical Medicine, Medical Microbiology and

Pharmacology

U N I V E R S I T Y O F H A W A I ‘ I A T M Ā N O A

Honolulu, Hawaii

dewolfe@hawaii.edu

HCV in Egypt Web Site

F. DeWolfe Miller• I am a tenured full professor of epidemiology and tropical medicine here at the

University of Hawaii• In 1972 I got a job at Pahlavi Medical School, Shiraz, Iran where I met Dr. Denis

Burkett. • In 1975 I moved to Cairo and for the next 4 years worked on the epidemiology of

schistosomiasis and the impact of the Aswan High Dam. It turned out that the Dam had little if any impact on schistosomiasis epidemiology in Egypt.

• I continued off and on working and living in Egypt on schisotosomiasis and started the Schistosomiasis Research Project.

• During that time an Egyptian colleague and I discovered that 10% of the Egyptian blood supply was positive for HCV. In the meantime I had moved from the University of Michigan faculty to UH.

• In 2008 I had a senior Fulbright Fellowship to Egypt to work on the epidemiology and control of HCV.

• In August 2010 we published an estimate of HCV incidence in Egypt in PNAS

Learning Objectives• Learn about the hepatitis C virus (HCV)

• Learn the importance of HCV in Egypt

• Understand how the epidemic of HCV in Egypt was discovered

• Understand the uniqueness of this epidemic and the role of iatrogenic transmission.

• Learn about measures to reduce HCV transmission in Egypt

Performance Objectives• To be able to explain the HCV epidemic in

Egypt to others• Know and explain the routes of HCV

transmission• To be able to critically assess the

epidemiologic literature published about this epidemic.

• Be able to devise public health measures to prevent HCV in Egypt

HEPATITIS C VIRUS (HCV)

THE VIRUS

• HCV is a small (50 nm in size), enveloped, single-stranded, positive sense (+ss)RNA virus– Small even for viruses

• Classified in the family Flaviviridae (includes Yellow and Dengue fevers)

• Subdivided into 6 genotypes (1 – 6) which have specific geographic distributions

• The major genotype in Egypt is 4.

HCV is a Blood borne pathogen

• Transmission of HCV from person to person is by blood:

• HCV is a Blood borne pathogen• Mother to new borne transmission also occurs. • Very little if any sexual transmission• HCV has no known reservoir in animals• HCV is found only in humans

Discovery of HCV in Egypt

• The first HCV ELISA tests became available in Egypt in 1992.

• These kits were being donated by Abbot throughout Europe and the Middle East.

• Nothing at the time was known about the occurrence of HCV in Egypt.

• Dr. Moamena Kamel, Professor clinical pathology, Kasr El Aini and Dr. F DeWolfe Miller

• Designed a study to examine first time health blood donors for HCV from donation campaigns around Cairo.

14,000 FIRST TIME HEALTHLY BLOOD DONORS IN CAIRO 1992

Over all

• 10.8% were confirmed HCV antibody positive• Prevalence increased by age• Logistic regression fit age specific prevalence• THIS WAS A BIG DEAL• Not only for blood donor recipients but a huge cost

increase to the blood supply system. • If you are in Egypt and you only have cross

matched blood that is HCV + what do you do?

Comparisons with other countries

• Global estimates of HCV ~ 200,000,000 persons. Under 2% total.

Percent Prevalence

• USA ~ 1.8%• Germany ~ 0·6%,• Canada ~ 0·8%• France ~ 1·1%• Australia ~ 1·1%• Japan ~ 1·5–2·3% -community micro epidemics

• Italy ~ 2·2%• Egypt blood donors 10.8%

Implications

• That the results from apparently healthy first time donors also suggested that 10.8% was likely an Under estimate of the true prevalence.

• People who donate blood (unpaid) will likely consider themselves healthy. People who consider themselves not healthy will likely not donate blood.

• This is a type of selection bias.

Village study

• Very rapidly Drs Kamel and Miller designed and completed a cross sectional study

• This was carried out in a village • Village location was in a remote area of the

northern Nile Delta• Everyone in the village was invited to participate. • Portable ultrasound examination of liver, spleen

and bladder was included & US done on everyone that participated

Google Egypt: approximate village location

Village north Nile Delta n=1,278

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Summary of results

• Over all prevalence 18.7%• Prevalence increased with age• Logistic regression best fit • Gender roughly equal• This is a population study not just healthy

blood donors• What inferences can be made?• Citation: Kamel MA, Miller FD et al. 1994. The epidemiology of S. mansoni, hepatitis B, and

hepatitis C infection in Egypt. Annals of Tropical Medicine and Parasitology 88 (5) 501-509.

Rural community study• The results strongly suggested that the high prevalence

of anti-HCV seen in the urban blood donors was likely to be the case throughout the county

• That is to say, nationally, the prevalence of anti-HCV was likely to be very high.

• At the time it was not known if there were variations in prevalence in different parts of the country, due to the lack of a representative national sample

• No association or correlation was seen between HCV

and schistosomiasis infection or liver pathology on ultrasound.

• There was an association with a history of percutaneous exposures.

Hepatocellular carcinoma HCC

• It had been known, for more than a decade, that chronic infection with HBV was the principle cause of primary liver cancer in the world (HCC)

• Immunization against HBV prevented HBV infection and subsequently HCC.

• Although hypothesized, at the time nothing had been published in the medical literature regarding the role of HCV and hepatocellular

• The HCC study followed

HCC Case Control study• 54 consecutive cases of histopathologically

confirmed primary hepatocellular carcinoma were identified and invited to participate in the study from Kasr El Aini in about two weeks.

• Each patient was tested for anti-HCV.• The residence (urban / rural ) and other

demographic data were obtained.• For urban residents – blood donor data were

used as a population base control• For rural residents – rural data were used as

control.

HCC Case Control study

Odds Ratio Odds Ratio

Village Urban

Exposure Controls Controls

HCV crude 2.1 3.2

HBsAg crude 4.3 3.7

HCV and HBsAg 1.3 2.4

HCV only 4.2 5.9

HBsAg only 25.0 12.1HCV only+ aFP>20 5.2 7.5

HBsAg only + aFP>20 70.0 33.8

HCV only + rural 4.1 5.9

HCV only+ aFP>20 + rural 12.9 18.3

HCV only + urban NA 5.3

HCC Case Control study

• This was the first ever observed association of HCV with HCC.

• There was an independent association of HCV with HCC.

• HBsAg was also strongly associated with HCC and serves here as an external validity control.

• Because HBsAg prevalence is more than 5 times lower than HCV prevalence, most of HCC in Egypt is attributable to HCV.

• Kamel and Miller (correspondence)

Why is HCV so high in Egypt

• An Association of HCV with previous parenteral treatment for schistosomiasis had been reported by Kamel et al and others.

• This observation was a key to a possible explanation for the high levels of HCV prevalence seen in Egypt.

• More than 50 years ago Egypt in an effort to control the morbidity caused by endemic schistosomiasis implemented large rural treatment campaigns.

• Parenteral anti-schistosomal therapy (PAT) campaigns throughout the endemic rural areas of Egypt in which multiple IV injections were given to thousands of patients.

• This was long before disposable needles and syringes were available and it has been hypnotized that the reused injection equipment was contaminated and widely transmitted HCV. Seeding an epidemic as it were.

The Frank et al. Lancet 2000

Lancet 2000; 355: 887–891

“The data suggest that PAT had a major role inthe spread of HCV throughout Egypt. This intensive transmission established a large reservoir of chronic HCV infection, responsible for the high prevalence of HCV infection and current high rates of transmission. Egypt’s masscampaigns of PAT may represent the world’s largest iatrogenic transmission of blood-borne pathogens.”

The Frank et al. Lancet 2000

• This report created a huge amount of press media inside and outside of Egypt.

• Other reports followed with the clear intent to confirm (rather than refute) this report

• The report has become “scientifically” popular

Cont. 1

• Many epidemiologists remain skeptical– Ecologic study design [weak]: generates hypothesis

only: paper did not point out limitations– Used available data: not based on original data

collection– Weak association: OR = 1.3– Many in Egypt have interpreted the results to mean

that HCV is no longer transmitted as PAT replaced 20+ years ago

– The results implied that iatrogenic transmission is no longer occurring.

– This was not good for public health measures to control HCV

Cont. 2

• At the same time as PAT, there was a exponential increase in the use of reusable glass syringes and needles and other parenteral procedures.

• The Lancet study did not rule out concurrent iatrogenic transmission by other percutaneous or partenteral procedures.

• The study provided no information on current HCV transmission in Egypt which is continuing

• Almost half the population in Egypt is urban (41%)• Schistosomiasis has never been urban• Yet the prevalence of HCV in urban populations is epidemic• The differences between urban and rural prevalence may be

confounded by SES.

Cont. 3

• Main objection to this study was: – Provided no information on current transmission and

– implied that iatrogenic transmission is no longer occurring.

– Impeded public health interventions

– Lead to a false sense of security

• Several studies followed from NAMRU 3 in Cairo showing wide spread iatrogenic exposures and generally poor to non existent infection control

• Two prospective studies in selected rural communities estimated HCV incidence at 6.1 and 5.0/1000.

• With a national population of ~ 80 million this computes to ~ 400,000 new HCV cases a year.

2009 National Study

• For the first time since the initial report of HCV in 1992 a national study of HCV prevalence was completed.

• This study was piggy backed on the Egyptian Demographic Health Survey study

• The study design was based on a representative sample of the entire country with large sample size.

• HCV antibody and RT-PCR HCV RNA was included.

• The DHS study estimated 14.7% of the Egyptian population were positive for HCV antibody and 10% positive for HCV RNA

Egypt

14.7%

Age specific prevalence of anti-HCV and HCV RNA from the DHS study

Does this graph look familiar? It should. It has the same shape as all previous studies.

The Next Question Was How MuchTransmission is occurring

• The previous two prospective studies were limited to selected rural communities.

• How many new infections of HCV are occurring in Egypt as a whole?

• Transmission is measured epidemiologically as Incidence• Or the number of new HCV cases per time period (year).• Epidemiological this is a huge challenge.

– First acute cases of HCV are rare. That is when most people become infected they do not become acutely ill. The initial infection is essentially silent.

– At a 6/1000 rate, large population need to be followed for extended periods.

– A national prospective study is not feasible

Estimating HCV Incidence

• The alternative is to estimate incidence from a model

• We used the methods described by:

• Zou S, Fang CT, & Dodd RY (2008) A method for estimating incidence rate of infectious diseases among first-time blood donors. Transfusion 48: 1827 - 1832.

• Leske M, Ederer F, & Podgor M (1981) Estimating incidence from age-specific prevalence in glaucoma. American Journal of Epidemiology 113: 606-613.

• This was published in the Proceedings of the National Academy of Science in August 2010.

• The study included a review of all reports of HCV prevalence in Egypt

Summary

• HCV is continued to be transmitted at epidemic levels in Egypt.

• Awareness campaigns are misdirected at the public instead of at the medical dental care system.

• Intervention should be directed at reducing exposure to blood at the health care patient interface.

• There is substantial literature supporting this intervention. • For more information on HCV control in Egypt please visit

www.hcvEgypt.com