Introduction
Hepatitis C (HCV) is now estimated to infect approximately 170 million people worldwide. It is five times more widespread than infection with human immunodeficiency virus type 1. In the developed world, it is emerging as a significant cause of end stage liver disease and a leading indication for liver transplantation¹. Reports from the US predict that morbidity and mortality from the infection are set to double over the next twenty years, with a substantial impact on health services anticipated².

The natural history of HCV infection has been the area of much research and debate. Progression to cirrhosis in as many as 20% of those with active viraemia after a period of twenty years has been predicted³. Different rates of disease progression between individual cohorts studied would suggest that the effect of infection is modified by a number of host and environmental variables. Factors shown to accelerate natural history include alcohol, co-infection with hepatitis B or HIV, older age at inoculation and male gender.⁴

With improvement in blood donor screening, injecting drug use (IDU) is the leading source of new HCV infection. The measured prevalence of HCV antibodies in Ireland for this group is between 62% and 84%^(5-7), but the proportion of this cohort with active viraemia (PCR, Polymerase Chain Reaction positive) has not been published. It is this group with persistent active viraemia who are truly at risk of serious sequelae.

The aims of this study were

1. to estimate the prevalence of persistent hepatitis C viraemia and distribution of genotypes in a drug using cohort,
2. to measure the frequency of poor prognostic co-factors, and
3. to extrapolate the burden of hepatitis C related disease in Ireland for this route of infection.

Subjects and methods
All patients registered with two practitioners at a community based drug treatment clinic in the East Coast Area Health Board in November 2001 were selected as the study group. Charts were reviewed and details on demographics, drug use characteristics, virology, and liver biochemistry results were recorded.

The AUDIT questionnaire was applied to subjects who were HCV antibody and PCR positive by a single interviewer. This instrument has been used to identify problem drinkers in the setting of hospital, general practice and amongst those with a problem of substance misuse^18-10.

The extrapolation of risk of cirrhosis and other complications was based on published figures for the prevalence of opiate dependency in Ireland¹¹ and the occurrence of cirrhosis, and its complications, amongst HCV infected cohorts^12,13.

Results
In total 94 subjects were identified and details of their demographic and substance misuse history variable are shown in Table 1.

HCV antibody status had been determined in 91 subjects. Of the seventy who were positive, PCR status to confirm active viraemia had been determined in 59 subjects; genotyping was available in all but two who were PCR positive. The results of HCV markers are presented in Table 2.

Figure 1 The frequency of poor prognostic co-factors in the HCV PCR positive group

Established co-factors for poor prognosis of HCV infection include male gender, alcohol excess, co-infection with hepatitis B or HIV, presence of a genotype which displays a poor response to treatment, long duration of infection, older age at inoculation and abnormal liver biochemistry. Figure 1 displays the measured frequency of these co-factors in those who had active viraemia (i.e. were PCR positive). For this purpose, a long duration of infection was defined as greater than ten years since the reported age of first injection, older age at first injection was defined as over thirty years of age, and abnormal liver biochemistry (LFTs) were defined as an elevation in one or more of GGT, ALT or AST of more than 1.5 times the upper limit of normal.

The majority of subjects with persistent viraemia display characteristics associated with poor outcome from HCV infection, predominantly male gender and problem drinking (71.8% and 83.3% respectively). Most already display evidence of hepatic dysfunction with abnormal liver biochemistry measured in 87.2%. Genotype one displays a poor response to current anti-viral regimens versus other genotypes, and it was found in 66.6% of subjects. In 35.8% of subjects over ten years had elapsed since first reported injection marking a longer incubation period in this sub-group and further advancement into the natural history of infection. Older age at inoculation and co-infection with hepatitis B or HIV were infrequent at 5.3% each.

Based on our results and published data we estimated the long term burden of HCV related disease among injecting drug users in Ireland. The prevalence of opiate dependency in Ireland is approximately 13,460 (95% Confidence Interval: 12,037-15,306, based on 1996 data)¹¹. Applying the prevalence of viral markers measured in this study, this would represent 5,519 (41%) subjects who are HCV PCR positive, and at risk of serious sequelae. After 20 years of persistent viraemia, it has been estimated that as many as 22% of subjects will develop HCV related cirrhosis¹². This would represent 1,214 cases nationally. Once HCV related cirrhosis has been established, a four year prospective follow up has estimated the complications of hepatocelluar carcinoma, hepatic decompensation and liver related death to occur at a frequency of 11.5%, 20% and 16% respectively¹³. This would equate to approximately 35 cases of hepatocellular carcinoma, 60 cases of hepatic decompensation, and 50 liver related deaths per annum.

Discussion
Injecting drug users are behaviourally vulnerable to acquisition of blood borne viruses, and a high prevalence of antibodies indicating previous exposure to HCV has been well established in this group both nationally^5-7 and internationally¹⁴. The seroprevalence rate of 74% described for our cohort is in keeping with this. The PCR status of those displaying antibodies to HCV is vital in assessment of risk for development of end stage liver disease. It is this sub-group who fail to spontaneously clear the virus, and suffer persistent active viraemia, who are truly at risk of serious sequelae. The prevalence of viral markers measured in our study would indicate that approximately half injecting drug users have persistent viraemia. This may be an under-estimate as PCR analysis was not performed on site of blood collection so there is a risk that some samples may have degraded before testing leading to false negative results.

The prevalence of cirrhosis observed in various natural history studies has been wide ranging: as low as 1.9% for community based female cohorts inoculated by contaminated blood products¹⁵to 21.4% for large liver clinic based cohorts¹⁶. Clearly, the development of end stage liver disease is dependent on a number of factors. We surveyed the frequency of some of these to develop a profile of risk for the study group. HCV infection is compounded by a high frequency of factors which are associated with a poor prognosis. The majority are male, many have probably carried infection for over ten years, and two thirds carry the genotype which shows the least favourable response to anti-viral therapy.

Predominant amongst these poor prognostic co-factors is alcohol excess. 83.3% of those who were HCV PCR positive were identified as problem drinkers by the AUDIT questionnaire. This instrument was devised to identify problem drinking in subjects with normal livers: it is possible that subjects with HCV who are not identified as problem drinkers by the questionnaire may still be drinking unsafely. Alcohol has been shown in a number of studies to have a significant impact on HCV related disease progression^17,18. We did not measure the frequency of problem drinking in those who were PCR or sero-negative and cannot comment on the impact which HCV status has on alcohol consumption in our sample. Evidence from the UK would suggest that HCV status can attenuate alcohol consumption in opiate users¹⁹. Active intervention to target alcohol consumption could potentially modify the outcome of HCV infection in this group.

The preponderance of co-factors for a poor prognosis in our sample would indicate a high likelihood of accelerated disease progression and result in a heavy burden on disease from IDUs infected with HCV nationally. This is demonstrated in our extrapolation which would estimate approximately 50 liver related deaths per annum from individuals infected with HCV through this route. To place these figures in context, for the year 2001 one hundred and seventeen deaths were registered as being related to liver disease, viral hepatitis, alcoholic cirrhosis of the liver and non-alcoholic cirrhosis of the liver (Central Statistics Office, personal communication). We applied a rate estimated from a systematic review of published epidemiological studies that incorporated assessment for cirrhosis¹². The result for liver clinic series was applied as the characteristics of these cohorts were best aligned with our study group in terms of gender balance, the preponderance of problem drinking and abnormal liver biochemistry.

Hepatitis C infection is a treatable disease. Not only can anti-viral therapy clear the virus²⁰, but it can reduce the rate of hepatic fibrosis²¹, prevent the complications associated with end stage liver disease¹³ and improve survival²². While a sustained virological response can be obtained in up to 82% of those with genotype 2 or 3, a poorer response rate is seen in those with genotype 123. Consensus statements from the US and Europe recommend withholding anti-viral therapy from illicit drug users until use has ceased for six months^24,25. Whether arguments behind these statements as policy are justifiable, or whether they promote tacit withholding of medical treatment from an already stigmatized group, is arguable²⁶. Retrospective analysis of the uptake of hospital services by ex-intravenous drug users with hepatitis C showed that anti-viral therapy was commenced in only half those in whom it was indicated with a substantial proportion of patients defaulting from follow up or declining further intervention²⁷. However, a prospective study of antiviral treatment in IDUs performed in close liaison between specialists in hepatology and substance misuse has shown encouraging compliance and response rates²⁸. Interestingly, there was no re-infection in those who relapsed to heroin injection after treatment in the latter study.

In conclusion, our analysis confirms a high seroprevalence for HCV in an Irish IDU cohort and demonstrates a profile of risk which predicts an accelerated progression of disease for this group. The heavy burden of disease which will result will have a significant impact on personal health. There will be a bearing on public health in terms of service provision and cost. In addition, those currently infected serve as a reservoir for the community at large. Harm reduction programmes including methadone treatment, education and needle exchange have shown an impact on the prevalence of HCV in this group and need to be maintained²⁹. Lastly, for those infected, modifiable outcome factors should be addressed with intervention targeting harmful drinking and optimal delivery of antiviral therapy through a patient-centred approach.

Correspondence:
PA McCormick,
The National Liver Unit, St. Vincents Hospital, Elm Park, Dublin 4.

1. Georg M. Lauer and Bruce D. Walker. Hepatitis C Virus Infection. N Eng J Med 2001 July; 345(1): 41-52.
2. John B. Wong, Geraldine M. McQuillan, John G. McHutchinson and Thierry Poynard. Estimating Future Hepatitis C Morbidity, Mortality, and Costs in the United States. Am J Pub Health 2000 Oct; 90(10): 1562-1569
3. EASL International Consensus Conference on Hepatitis C. Consensus Statement. J Hepatol 1999; 30: 956-961
4. Adrian M. Di Bisceglie. Natural History of Hepatitis C: Its Imapact on Clinical Management. Hepatology 2000 April; 31(4): 1014-1018
5. Bobby P. Smyth, Eamon Keenan and John J. OConnor. Bloodborne viral infection in Irish injecting drug users. Addiction 1998; 93(11): 1649-1656.
6. M. Fitzgerald, J. Barry, P. OSullivan, L. Thornton. Blood-borne infections in Dublins opiate users. Ir J Med Sci 2001; 170: 32-34
7. R. Smyth, E. Keenan, A. Dorman, and J. OConnor. Hepatitis C infection among injecting drug users attending the national drug treatment centre. Ir J Med Sci 1995; 164: 267-268
8. Saunders JB. Aasland OG, Babor TF, de la Fuente JR, Grant M. WHO Collaborative Project on early detection of persons with harmful alcohol consumption. Addiction 1993; 88: 791-804
9. MacKenzie D M, Langa A, Brown T M. Identifying hazardous or harmful alcohol use in medical admissions: a comparison of AUDIT, CAGE and Brief MAST. Alcohol and Alcoholism 1996; 31: 591-599
10. Skipsey K, Burleson J A, and Kranzler H R. Utility of the Audit for identification of hazardous or harmful drinking in drug dependent patients. Drug and Alcohol dependence 1997; 45: 157-163)
11. Comiskey CM, Barry JM. A capture-recapture study of the prevalence and implications of opiate use in Dublin. Eur J Public Health 2001 Jun;11(2):198-200
12. Freeman A J, Dore G J, Law M G, Thorpe M, Von Overbeck J, Llyod A R, Marinos G, Kaldor J M. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001; 34: 809-816.
13. Serfaty L, Aumaitre H, Chazouilleres o, Bonnand A M, Rosmorduc O, Poupon R E and Poupon R. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology 1998;27: 1435-1440.
14. Wodak A. and Crofts N. Once more onto the breach: controlling hepatitis C in injecting drug users. Addiction 1996; 91: 181-184
15. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Eng J Med 1999; 340: 1228-1233
16. Roudot-Thoraval F, Bastie A, Pawlotsky JM, Dhumeaux D. Epidemiological factors affecting the severity of Hepatitis C virus related liver disease: a French survey of 6,664 patients. The Study for the Prevalence and Epidemiology of Hepatitis C virus. Hepatology 1997; 26: 485-490
17. Ostapowicz G., Watson K.J.R., Locarnini S. A., and Desmond P. V. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998; 27(6): 1730-1735
18. Wiley T.E., Mc Carthy M. Breidi L., Mc Carthym, and Layden T. J. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998; 28(3): 805-809
19. McCusker M. Influence of hepatitis C status on alcohol consumption in opiate users in treatment. Addicition 2001; 96: 1007-1014
20. Zeumem S, Feinman S V, Rasenack J, Heathcote E J, Lai M Y, Gane E, OGrady J, Reichen J, Diago M, Lin A, Hoffman J, Brunda MJ. Peginterferon alfa-2a in patients with chronic hepatitis C. N Eng J Med 2000; 343: 1666-1672
21. Poynard T, McHutchinson J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling M, and Albrecht J for the PEG-FIBROSIS Project Group. Impact of pegylated interferon alfa-2b and ribaviran on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122(5):1303-1313.
22. Yoshida H, Arakawa Y, Sata M, Nishiguchi S, Yano M, Fujiyama S, Yamada G, Yokosuka O, Shiratori Y, Omata M. Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology 2002 Aug;123(2):483-91
23. Manns M P, McHutchinson J G, Gordon S C, Rusti V K, Shiffman, M, Reindollar R, Goodman Z, Koury K, Ling M, Albrecht J. PEG interferon alfa -2a in combination with ribaviran compared to interferon alfa-2a plus ribaviran for initial treatment of chronic hepatitis C. Lancet 2001; 358: 1426-1432.
24. National Institutes of Health consensus development conference panel statement: management of hepatitis C. Hepatology 1997; 26(suppl): 71S-77S
25. EASL international consensus conference on hepatitis C. Consensus Statement. J Hepatol 1999; 30: 956-961
26. Edlin B R, Seal K H, Lorvick J, Kral A H, Ciccarone D H, Moore L D, Lo B. Sounding board: is it justifiable to withhold treatment for hepatitis C from illicit-drug users? N Eng J Med 2001 July; 345(3):211-214.
27. Jowett S L, Agarwal K, Smith B C, Craig W, Hewett M, Sassendine D R, Gilvarry E, Burt A D, and Bassendine M F. Managing chronic hepatitis C acquired through intravenous drug use. Q J Med 2001; 94: 153-158
28. Backmund M, Meyer K, Von Zielonka and Eichenlaub D. Treatment of hepatitis C infection in injection drug users. Hepatology 2001; 34: 188-193.
29. Smyth B P, Keenan E, OConnor J J. Evaluation of the impact of Dublins expanded harm reduction programme on the prevalence of hepatitis C among short-term injecting drug users. J Epidemiol Community Health 1999;53: 434435.